Design, synthesis and anti-rheumatoid arthritis evaluation of double-ring conjugated enones

Bioorganic Chemistry 109 (2021) 104701

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Bioorganic Chemistry

journal homepage: www.elsevier.com/locate/bioorg

Design, synthesis and anti-rheumatoid arthritis evaluation of double-ring

conjugated enones

,

b

,

,b,*

Shiyang Zhou^{a c}, Huiying Zou^{a b}, Gangliang Huang^{c *}, Guangying Chen^a

,

Xueming Zhou^{a b}, Shuheng Huang^d

^aKey Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571127,

China

^bKey Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, Hainan Normal University, Haikou 571158, China

^cCollege of Chemistry, Chongqing Normal University, Chongqing 401331, China

^dCollege of Bioengineering, Chongqing University, Chongqing 400044, China

A R T I C L E I N F O

A B S T R A C T

Keywords:

Four series of double-ring conjugated enones were designed, synthesized and studied for the inhibition of sy-

novial cell activity through the modiﬁcation of Dysodensiol K core structure, double-ring, double-bond and

double-carbonyl groups. For in vitro synovial cell assay of rats, compound 151 and 168 exhibited good inhibitory

Conjugated enones

Modiﬁcation

Synovial cell

Design

activities, with IC₅₀values of 2.71 ± 0.18 and 2.68 ± 0.16 μM respectively. At the same time, the LDH release

and LD₅₀test results revealed that the target compounds were low cytotoxicity and acute toxicity. For in vivo CIA

model test through the oral administration, compounds 151 and 168 were exhibited similar effect to positive

control group methotrexate.

Synthesis

1. Introduction

articular cartilage, joint ligament, bone tissue and muscle bond. It can be

further affect by the extensive inﬂammatory disease of connective tissue

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune

disease, and characterized by synovitis of the joints [1–3]. Repeated

attacks of synovitis can lead to the destruction of cartilage and bone

joints, joint dysfunction, and even disability. Although the RA is not

malignant, it imposes a heavy burden on the patient and the family as

the patient has recurrent episodes that eventually lead to joint malfor-

mations and loss of function. RA not only brings physical unbearable

pain, distortion, swelling of joints and trauma to the patients, but also

mental devastation [4]. Once the disease is severe, the sufferer will be

unbearable pain. So once the body is not must be timely intervention

treatment. However, the majority of patients even RA pathogenic factors

are not clear, how difﬁcult to talk about treatment. The early clinical

manifestations of RA is relate to joint redness, heat, pain, swelling and

dysfunction. In late stage, different degrees of deformity and stiffness of

joints may occur, accompany by atrophy of the bone and skeletal mus-

cle, which is very likely to cause disability [5]. RA onset age mostly in

20–60 years old age and the incidence of women than men. From the

point of view for pathological changes, RA is a major involve synovial

membrane of the joint. After the severity of the disease can affect the

such as heart, lung, serous membrane and eye. In addition to joint le-

sions, RA systemic manifestations of fever, pericarditis, fatigue, pleurisy,

subcutaneous nodules, peripheral neuropathy and arteritis, etc [6–8].

The etiology of RA is not completely clear, it is closely related to the

environment, genetics, viruses and sex hormones factors [9]. The

pathogenesis is not completely clear, but it is generally recognize as an

autoimmune disease. Although the tissue changes of the RA may vary

slightly due to the location, the basic changes are the same [10–12].

The main purpose of RA treatment is to reduce the inﬂammatory

reaction of joints. Inhibit the development of lesions and irreversible

bone destruction, protect the function of muscles and joints as much as

possible. Finally, achieve the goal of complete reduction or remission of

disease activity [13]. Currently, RA is an incurable disease and the

common drugs used are generally divided into ﬁve categories: 1) Non-

steroidal anti-inﬂammatory drugs (NSAIs), which have to beanalgesic

and anti-inﬂammatory, which could reduce the symptoms of arthritis,

but cannot control the condition. At such a situation, it is suggested to

change the anti-rheumatoid drug. 2) Slow-acting anti-rheumatoid drugs

(SAARs) can play a role in controlling the course of rheumatoid arthritis.

* Corresponding authors.

E-mail addresses: huangdoctor226@163.com (G. Huang), chgying123@163.com (G. Chen).

https://doi.org/10.1016/j.bioorg.2021.104701

Received 15 December 2020; Received in revised form 29 January 2021; Accepted 30 January 2021

Available online 9 February 2021

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

3) Glucocorticoids (GCs) have a powerful anti-inﬂammatory effect,

which can quickly relieve systemic inﬂammation, joint swelling and

pain. 4) Targeted therapy with biological agents. 5) Botanical medicine

preparation [14–16]. Clinically, the pain associate with RA is very se-

vere. Therefore, when this happens, the patients should be treated with

NSAIs in time, such as dichlorfenic acid, nabumetonen and meloxicam.

In addition, SAARs can be treated with RA, such as methotrexate and

sulfasalazine. If the patient’s condition is more serious, it is recom-

mended to use GCs and biological agents for treatment. At present, there

have been a variety of plant drugs for RA, such as sinomenine, trip-

terygium wilfordii, etc. Some plant drugs are effective with treatment

RA, but the mechanism of action needs further study. Dysodensiol K is a

monomer compound and isolate from Fissistigma oldhamii with anti-

rheumatoid arthritis activity. Its inhibitory effect on synovial cells can

rheumatoid arthritis treatment drugs. Dysodensiol K was a natural

product isolated from medicinal plant (Fissistigma oldhamii) and it had

shown a good inhibitory effect on synovial cells growth during the

screening of anti-rheumatoid arthritis activity in vitro. Due to the low

content of natural products, it also limits the further research and

development of drugs [27]. In view of Dysodensiol K was a good anti-

rheumatoid arthritis activity, we analyzed its chemical structure and

found that it had a double-ring conjugated enone structure (double-ring,

double-bond and double-carbonyl groups). In order to ﬁnd a large

number of compounds that could be screened for anti-rheumatoid

arthritis activity in vitro, we turned to chemical synthesis. We took

Dysodensiol K as the lead compound and modiﬁed its structure,

designed four series of 98 target compounds (Fig. 1). In the design

process of the target compounds (41–78 and 139–198), we retained the

basic skeleton structure of Dysodensiol K (double-ring conjugated enone

structure). So as to ensure the anti-rheumatoid arthritis activity of the

designed target compounds to a greater extent. In order to obtain the

ideal target compounds with anti-rheumatoid arthritis activity, intro-

duced different substituents at different positions of the aliphatic ring to

study the structure–activity relationship (SAR) of the drugs. In the

process of synthesis the target compounds, we chose a synthetic route

with better synthetic efﬁciency (Scheme 1 and Scheme 2). Four series of

target compounds were synthesized from ethyl acetoacetate (compound

1a) and ethyl levulinate (compound 1b) by four steps of carbonyl pro-

tection, condensation, hydrolysis and cyclization. First of all, compound

1a and compound 1b were placed in benzene and carbonyl protected

with ethylene glycol. In this step, p-methylbenzenesulfonic acid (p-

TsOH) was used as catalyst and reﬂux reaction lasted for 48 h to obtain a

relatively ideal yield (more than 98% yield). After the compounds 2a

and 2b were obtained, it were placed in anhydrous ethanol and treated

with different substituted cyclopentanone (Scheme 1, 1 and 2 series

target compounds 41–78) or cyclohexanone (Scheme 2, 3 and 4 series

target compounds 139–198). During the treatment, sodium ethanol was

used as an alkaline substance and reﬂuxed for 12 h. After the conden-

sation reaction was completed and solvent was removed. The hydro-

chloric acid solution was directly hydrolyzed to remove the carbonyl

protection, and the corresponding intermediates (compounds 3–40 and

79–138) could be obtained (56.7%-92.1% yield). Finally, compounds

3–40 and compounds 79–138 were placed in anhydrous ethanol and

reach IC₅₀= 11.8 ± 0.23 μM in vitro (Fig. 1) [17–19]. In the further study

of the mechanism of action, it is found that the Dysodensiol K has a good

binding to Toll-like receptor 4 (TLR4). Thus, inhibiting the growth of

synovial cells and playing a role in the treatment of RA [20–25]. In this

study, Dysodensiol K was used as the lead compound to modify the

chemical structure to ﬁnd a more ideal target compounds with anti-

rheumatoid arthritis activity. Four series of double-ring conjugated

enones were designed (Fig. 1) and these target compounds (compounds

41–78 and compounds 139–198) were screened for anti-rheumatoid

arthritis activity tests in vitro, including rat synovial inhibitory activ-

ity, LDH cell activity tests. On this basis, in vivo anti-rheumatoid arthritis

activity tests were carried out on the ideal target compounds with anti-

rheumatoid arthritis activity in vitro. At the same time, the molecular

docking simulation studies were used to explain the degree of binding

between the target compounds and TLR4. It can be providing a certain

theoretical basis for the design of such compounds [26].

2. Results and discussions

2.1. Design and synthesis

Further separation of small molecule and monomer compounds from

active components of phytodrugs was an important part of modern

phytodrug chemistry. And as the lead compound, further structural

optimization and modiﬁcation, it could be obtained a more ideal anti-

Fig. 1. The design of double-ring conjugated enones.

2

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Scheme 1. Reagents and conditions: (a) ethanediol, benzene, p-TsOH, reﬂux 48 h; (b) substituted cyclopentanone, C₂H₅OH, C₂H₅ONa, reﬂux 12 h; (c) HCl, H₂O,

60℃, 2 h, (d) KOH, C₂H₅OH, reﬂux 12 h.

Scheme 2. Reagents and conditions: (a) ethanediol, benzene, p-TsOH, reﬂux 48 h; (b) substituted cyclohexanone, C₂H₅OH, C₂H₅ONa, reﬂux 12 h; (c) HCl, H₂O,

60℃, 2 h, (d) KOH, C₂H₅OH, reﬂux 12 h.

reﬂuxed under the condition of potassium hydroxide as an alkaline

substance (reﬂuxed for 12 huorus). The target compounds 41–78 and

compounds 139–198 were obtained by silica gel column separation,

with an yield of 38.8%-89.2%. Meanwhile, in order to study the pres-

ence of enantiomers in the target compounds, we measured the e.e.

value of target compound 151, 156 and 168. The results showed that the

e.e. values of the compounds 151, 156 and 168 were relatively high,

which were 98.8%, 99.1% and 99.3%, respectively, which also indicated

that the design of the synthesis route was scientiﬁc and reasonable. The

synthetic route has relatively conventional operation, the solvents and

reagents used were cheap and easy to be obtained, no expensive catalyst

was needed, and the total yield of the target compounds were relatively

ideal. This synthetic route provides a certain experimental basis for

industrialization in the future, and facilitates the subsequent expansion

of output.

patients with RA. In the screening process of anti-rheumatoid arthritis

activity in vitro, the inhibitory activity of target compounds on rat sy-

novial cells was used as the evaluation index. The CKK assay was used to

determine the inhibitory effect of the compounds on rat synovial cells,

and the IC₅₀value was used to evaluate the anti-rheumatoid arthritis

activity of the target compounds in vitro. Dysodensiol K was a natural

product that had been shown inhibitory rat synovial cells activity. Its

inhibitory activity of IC₅₀= 11.8 ± 0.23 μM during in vitro screening

could be used as a potential treatment for RA or as a lead compound for

further structural optimization. Used Dysodensiol K as the lead com-

pound, we designed and synthesized four series of 98 target compounds

(1, 2, 3, 3a-tetrahydro-4H-indene-4, 6 (5H)-dione derivatives, com-

pounds 41–59; 1, 2, 3, 3a, 5, 6-hexahydroazulene-4, 7-dione derivatives,

compounds 60–78; 6, 7, 8, 8a-tetrahydronaphthalene-1, 3 (2H, 5H)-

dione derivatives, compounds 139–168 and 2, 3, 4, 4a, 6, 7-hexahydro-

1H-benzo [7] annulene-5, 8-dione derivatives, compounds 169–198)

[28]. And screened these compounds to inhibit the activity of rat sy-

novial cells in vitro, so as to evaluate the anti-rheumatoid arthritis ac-

tivity of the target compounds (41–78 and 139–198). In vitro screening

results showed that the most of target compounds could inhibit the

growth of rat synovial cells, with IC₅₀values ranging from 2.68 ± 0.16 to

2.2. Inhibition and morphology study of rat synovial cells in vitro

RA is a systemic disease with unknown etiology, and mainly in-

ﬂammatory synovitis. Synovial cells were important tissue structures to

maintain the normal function of joints and the main lesion sites in

3

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

10.64 ± 0.76 μM (Table 1). Among them, the compounds 44, 45, 56, 57,

Table 1

In vitro inhibition activity of rat synovial cells.

63, 64, 66, 67, 75, 78, 151, 156, 166, 168, 169, 171, 177, 178 and 195

showed ideal inhibitory activities, with IC₅₀values of 3.04 ± 0.26, 2.93

± 0.21, 3.04 ± 0.31, 2.93 ± 0.16, 3.19 ± 0.21, 2.95 ± 0.20, 3.21 ± 0.29,

3.05 ± 0.24, 3.19 ± 0.26, 3.26 ± 0.22, 2.71 ± 0.18, 2.86 ± 0.20, 2.98 ±

0.23, 2.68 ± 0.16, 2.92 ± 0.21, 2.97 ± 0.26, 3.12 ± 0.29, 3.07 ± 0.28

Compounds

Structure

logp

pK_a

IC₅₀

(

μ

M)^a± SD

41

1.35

8.3

3.49 ± 0.35

and 3.28 ± 0.32

pounds 151 (IC₅₀= 2.71 ± 0.18

showed inhibitory activity close to positive control methotrexate (IC₅₀

= 2.36 ± 0.22 M), which was at the same level as the inhibitory rat

μ

M, respectively. Among these compounds, the com-

42

43

1.66

2.11

8.3

8.2

4.22 ± 0.30

μ

M) and 168 (IC₅₀= 2.68 ± 0.16 M)

μ

3.29 ± 0.34

3.04 ± 0.26

synovial cells activity. Drugs generally combine with the receptors on

the cells of the body and then play a drug effect. Structure-activity

relationship (SAR) refers to the relationship between the chemical

structure of drugs or other physiologically active substances and their

physiological activities, which was one of the main research contents of

pharmacochemistry. Compound 41, 60, 139 and 169 has the parent

nucleus structure, its has the similar structure of the lead compound

Dysodensiol K. On the basis of compounds 41, 60, 139 and 169, the

structure of the junction was modiﬁed, increasing or decreasing ring,

and different substituents (electron-withdrawing group and electron-

donating group) were introduced into the aliphatic ring to study the

SAR of the compounds. The four series of parent compounds showed

good inhibitory activity in vitro, and their IC₅₀values were 3.49 ± 0.35,

44

2.56

8.2

45

46

2.43

2.90

8.2

8.1

2.93 ± 0.21

4.68 ± 0.35

3.23 ± 0.23, 3.12 ± 0.22 and 2.92 ± 0.21 μM, respectively. After the

optimization of the structure of the parent compounds in each series,

some compounds with better activity were also obtained, among which

the compounds in the third series were better as a whole, especially like

compounds 151 and 168. In order to visualize the inhibitory activity of

the target compounds in vitro, we studied the morphology of rat synovial

cells in vitro of target compounds 151, 156, 168 and 169 (Fig. 2).

Compared with the normal group, the morphology of rat synovial cells

in the DMSO group was not abnormal. The damage of rat synovial cells

in the positive control methotrexate group was signiﬁcant, the refractive

activity of the cells was decreased, the cytoplasm of the cells became

narrow and wrinkled, the ﬁbroblasts were signiﬁcantly reduced, some

cells were broken, and the number of cell fragments increased. Com-

pounds 151, 156, 168 and 169 group showed obvious damage to rats

synovial cells and different degrees of refraction, with cell cytoplasm

becoming narrow and shrunken, ﬁbroblasts decreasing signiﬁcantly,

some cells were broken and cell fragments increased, showing a good

effect of destroying synovial cells. Cell morphology studies could be

showed that the target compounds inhibit the growth of rat synovial

cells in vitro.

47

2.83

8.1

3.78 ± 0.32

48

49

2.88

3.15

8.0

5.48 ± 0.041

4.01 ± 0.36

50

3.91

7.9

3.37 ± 0.28

2.3. LDH release values of rat synovial cells in vitro

Lactate dehydrogenase (LDH) is one of the most important redox

enzymes in the glycolytic pathway of organisms. It could reversely

catalyze the oxidation of lactic acid to pyruvate[28]. LDH was an

extremely stable cytoplasmic enzyme, which mainly exists in the liver,

myocardium, skeletal muscle, kidney and lung tissues. LDH was abun-

dant in the cytoplasm, which cannot pass through the cell membrane in

normal times. But LDH could be released into the extracellular envi-

ronment when the cell dead or damage. The number of cell death was in

direct proportion to the LDH activity in the supernatant of cell culture.

Quantitative analysis of cytotoxicity could be achieved by detecting the

activity of LDH released into the culture medium from cell membrane

ruptured. LDH release was regarded as an important indicator of cell

membrane integrity, which could determine the degree of cell damage

and widely used in cytotoxicity detection. Compounds 44, 45, 56, 57,

63, 64, 66, 67, 151, 156, 166, 168, 169, 171, 177, 178 and 195 showed

ideal inhibitory activities during the screening process of inhibiting the

growth of rat synovial cells in vitro. Therefore, these compounds (con-

centration at 1 µM) were further tested for LDH release to evaluate the

degree of damage to rat synovial cells caused by the target compounds

(Table 2). Test results showed that the LDH release values of these

51

52

53

2.78

3.12

2.98

8.4

8.3

8.1

6.09 ± 0.51

4.94 ± 0.50

5.70 ± 0.53

54

0.89

8.6

3.96 ± 0.37

(continued on next page)

4

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Table 1 (continued)

Compounds

Structure

logp

pK_a

IC₅₀

(μ

M)^a± SD

Compounds

Structure

logp

pK_a

IC₅₀

(

μ

M)^a± SD

55

56

1.12

0.44

8.5

3.96 ± 0.35

3.04 ± 0.31

71

72

3.40

3.00

8.3

5.01 ± 0.40

4.40 ± 0.39

57

58

1.50

2.97

7.3

8.0

2.93 ± 0.16

3.16 ± 0.23

73

74

75

76

77

78

1.02

1.35

0.61

1.79

3.18

0.92

8.5

7.3

8.0

8.3

6.43 ± 0.43

3.77 ± 0.32

3.19 ± 0.26

4.33 ± 0.29

6.34 ± 0.41

3.26 ± 0.22

59

60

0.81

1.58

8.3

8.4

8.61 ± 0.68

3.23 ± 0.23

61

62

1.90

2.34

8.4

8.2

3.52 ± 0.22

3.64 ± 0.26

63

2.77

8.3

3.19 ± 0.21

139

140

1.57

1.91

8.2

8.0

3.12 ± 0.22

5.08 ± 0.43

64

65

2.66

3.15

8.3

8.1

2.95 ± 0.20

3.64 ± 0.28

141

142

1.92

1.90

8.0

5.33 ± 0.49

5.46 ± 0.45

66

3.08

8.2

3.21 ± 0.29

143

144

145

2.33

2.70

3.05

8.0

7.9

7.8

4.35 ± 0.40

3.82 ± 0.28

5.71 ± 0.51

67

68

3.13

3.59

8.1

8.0

3.05 ± 0.24

3.89 ± 0.31

146

147

3.11

3.57

7.8

7.9

3.94 ± 0.30

4.73 ± 0.41

69

70

4.32

3.01

8.0

8.5

4.19 ± 0.33

3.52 ± 0.26

148

3.51

7.9

4.14 ± 0.39

(continued on next page)

5

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Table 1 (continued)

Compounds

Structure

logp

pK_a

IC₅₀

(μ

M)^a± SD

Compounds

Structure

logp

pK_a

IC₅₀

(

μ

M)^a± SD

149

2.90

7.7

3.48 ± 0.26

166

0.39

8.9

2.98 ± 0.23

4.58 ± 0.50

2.68 ± 0.16

167

168

3.99

2.45

7.9

8.8

150

151

3.05

3.55

7.8

7.9

4.17 ± 0.33

2.71 ± 0.18

169

170

1.68

1.88

8.1

8.0

2.92 ± 0.21

4.46 ± 0.38

152

153

2.50

1.60

7.8

8.5

3.89 ± 0.37

3.29 ± 0.26

171

1.89

8.0

2.97 ± 0.26

172

173

174

1.87

2.38

2.69

8.0

8.1

7.9

4.05 ± 0.36

4.22 ± 0.39

4.24 ± 0.40

154

155

0.59

1.32

8.0

8.1

4.33 ± 0.41

3.37 ± 0.33

156

157

1.44

0.39

8.0

8.3

2.86 ± 0.20

4.96 ± 0.47

175

3.00

7.9

3.78 ± 0.35

176

177

3.06

3.55

7.8

7.9

4.11 ± 0.35

3.12 ± 0.29

158

159

1.35

1.70

8.6

7.6

4.68 ± 0.46

4.53 ± 0.49

178

179

3.48

2.88

8.0

7.7

3.07 ± 0.28

4.12 ± 0.38

160

161

162

2.33

2.76

2.63

7.7

7.8

3.56 ± 0.34

3.34 ± 0.36

3.51 ± 0.33

180

3.05

7.8

4.43 ± 0.40

163

164

2.59

2.93

7.6

7.8

3.55 ± 0.39

4.12 ± 0.39

181

182

4.35

2.49

8.0

7.8

3.19 ± 0.31

4.28 ± 0.41

165

0.50

7.9

6.24 ± 0.51

(continued on next page)

6

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Table 1 (continued)

Compounds

Structure

logp

pK_a

IC₅₀

(μ

M)^a± SD

Compounds

Structure

logp

pK_a

IC₅₀

(

μ

M)^a± SD

183

1.55

8.6

10.64 ± 0.76

methotrexate^b

a

—

2.36 ± 0.22

Values are the average of 3 independent experiments run in triplicate.

Methotrexate is use as positive control.

b

184

185

2.61

0.55

8.0

8.1

4.76 ± 0.39

6.65 ± 0.59

compounds were lower than those of the positive control methotrexate

(454.59 ± 19.75 U/L at 1 µM), indicating that these target compounds

had better cell membrane damage than the positive control substance.

The LDH release value of compound 63 was the lowest, it were 281.22 ±

22.84 U/L at 1 µM. It also showed that the inhibitory activity of the

target compounds on rat synovial cells was not caused by cytotoxicity,

and these compounds could be showed low cytotoxicity. Therefore,

these types of target compounds have further structural modiﬁcations,

in-depth study, including mechanism of action, pharmacokinetics, acute

toxicity and other related studies.

186

187

1.29

0.33

8.0

8.3

4.26 ± 0.43

5.18 ± 0.48

2.4. In vivo of anti-rheumatoid arthritis activity

In vitro screening of anti-rheumatoid arthritis activity, most of the

target compounds showed a good inhibition of rat synovial cells [29]. In

vitro activity results combined with LDH release values for the com-

pounds 151, 156, 168 and 169were necessary for anti-rheumatoid

arthritis in vivo testing. To determine the effectiveness of an animal

model for anti-rheumatoid arthritis in vivo, we used a collagen-induced

arthritis (CIA) model in rats. In a rat CIA model, we evaluated the

therapeutic effects of compounds 151, 156, 168 and 169, including paw

188

189

1.29

1.68

8.7

7.6

5.10 ± 0.51

4.81 ± 0.39

190

191

2.33

2.66

7.7

7.8

4.23 ± 0.38

3.78 ± 0.33

volume, IL-6 and TNF-α concentrations of serum. During the evaluation,

normal group, blank control group, positive control group (metho-

trexate, 50 mg/kg/day) and target compound groups (50 mg/kg/day

and 100 mg/kg/day) were set. In the paw volume evaluation of rats

(Fig. 3 and Fig. 4), the test results showed that the paw volume of the

induced inﬂammation rats was basically unchanged before and after the

treatment with the compounds 151, 156, 168 and 169 for high dose.

However, at low dose, compound 151 and 168 remained essentially

unchanged before and after treatment, while compound 156 and 169

showed a slight change in paw volume before and after treatment,

suggesting that compounds 151 and 168 might be more effective. As

could be seen from the real picture of the rat paw in Fig. 4, the blank

group (Fig. 4b) showed obvious redness and swelling, the paw became

signiﬁcantly larger, which was caused by inﬂammation. However, the

rats treated with the compounds 151, 156, 168 and 169 showed no

redness or swelling, the paw volume remained unchanged, reaching the

192

193

2.59

2.50

7.8

7.6

3.76 ± 0.39

3.89 ± 0.37

194

195

2.99

0.98

7.9

4.37 ± 0.41

3.28 ± 0.32

level of the normal group (Fig. 4a). In measuring IL-6 and TNF-α con-

centrations of serum (Fig. 5), the treatment with high and low doses of

compounds 151, 156, 168 and 169 showed improvement. Test results

show that the compounds 151, 156, 168 and 169 with treatment, the

concentration of IL-6 basic reached a consistent level. Compared with

normal group and positive control products in the same level, the con-

centration of IL-6 and blank control group has obvious improvement,

suggesting that compounds 151, 156, 168 and 169 have good anti-

rheumatoid arthritis activity in vitro. At the same time, the concentra-

196

197

0.62

4.59

9.0

7.9

3.78 ± 0.35

4.01 ± 0.36

tions of TNF-α in serum after treatment of compounds 151, 156, 168 and

169 were also improved compared with the blank control group, but

there was a dose dependence. The compounds 151 and 168 were rela-

tively most effective after high dose treatment, reaching the treatment

level of the positive control methotrexate. The meaning of symbols were

** = P less than 0.01, * = P less than 0.05.

198

2.26

8.8

4.09 ± 0.31

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Bioorganic Chemistry 109 (2021) 104701

Fig. 2. The morphology of rat synovial cells. a) normal group; b) DMSO group; c) methotrexate group; d) compound 151 group; e) compound 156 group; f)

compound 168 group; g) compound 169 group. The rat synovial cells were treated with different concentrations of test substances for 48 h, including the con-

centration at 5‰ of DMSO group, the concentration at 1

μ

M of methotrexate group and target groups. Morphological changes of synovial cells were observed on the

cell imaging analysis system (x 150).

2.5. In vivo of LD₅₀test

2.6. Binding modes of TLR4

Acute toxicity refers to the toxic effects caused by the body after one

or more exposure within 24 h to foreign compounds and even death

[30]. Acute toxicity test was the fundamental basis for understanding

the toxicity of exogenous chemicals on the body and the ﬁrst step of

toxicological safety evaluation. The purpose of the acute toxicity test

was to calculate the lethal dose of half (LD₅₀) of the tested substance

based on the data obtained from the test [31]. Explain the relative

toxicity and toxicity characteristics of the tested substance and the

dose–response relationship, and provide guidance for the dose used in

other experimental studies. To evaluate the safety of the target com-

pounds, we tested compounds 151, 156, 168 and 169 for acute toxicity

(Table 3). The in vivo safety of the compounds were evaluated by the

method of oral intragastric in mice. The acute toxicity test results

showed that the acute toxicity of the tested compounds was low in vivo

and signiﬁcantly reduced compared with the positive control substance

methotrexate. The LD₅₀of compound 168 was 2614.26 ± 9.19 mg/kg

and that of methotrexate was 1368.43 ± 5.34 mg/kg. The test of acute

toxicity provides the necessary theoretical basis for further toxicological

study.

In order to make in depth study of the binding modes between TLR4

and target compounds, interaction processes of TLR4 within four

representative compounds (151, 156, 168 and 169) were performed

through docking analysis by molecular dock [32]. As shown in Fig. 6a, it

could be seen that the binding pocket of co-crystalized antagonist Eri-

toran was consist of the most of hydrophobic residues of MD-2 and

partial interface residues of TLR4. The former pocket mainly combines

group with unsaturated and saturated fatty acid chains, while the latter

prefer to combine aromatic rings and carbonyl groups [33]. Considering

carbon and carbon-carbonyl heterocycles as the main structure of syn-

thetic compounds, binding pocket on TLR4 generated by 5 Å distance

from co-crystalized antagonist Eritoran was chosen as the binding drug

site to estimate interaction between TLR4-MD-2 complex and target

compounds. It could be observed that the protein contact potential and

hydrophobic lipophilic potential was asymmetrically distributed in the

ligand binding pocked. The lowest energy conformations of target

compounds 151, 156, 168 and 169 were displayed in Fig. 6b-6e, which

reveals small molecules tightly combine to TLR4-MD-2 complex inside

the hydrophobic cavity. It could be observed that the hydrogen bonding

and electrostatic interactions were the predominant forces to form the

protein-drug complexes, which the compound 168 form four H-bonds

with Thr319 and Arg262, compound 151 form tow H-bonds with

8

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

mainly formed by the carbonyl groups of compounds and charged side

chain of residues. Four residues, i.e. Thr319, Lys362, Arg262 and

Tyr292 play the important role in the binding site [34].

Table 2

The release values of LDH.

Compounds

Concentration

LDH activity (U/L)^a± SD

44

1 µM

5‰

351.39 ± 23.02

334.62 ± 16.98

309.86 ± 27.12

367.13 ± 10.92

281.22 ± 22.84

363.78 ± 23.78

333.85 ± 20.87

380.55 ± 13.63

316.56 ± 27.04

291.02 ± 18.96

370.05 ± 24.69

352.43 ± 8.15

333.33 ± 22.89

385.71 ± 18.30

352.68 ± 24.87

343.40 ± 24.87

332.04 ± 18.07

337.20 ± 19.68

324.05 ± 23.22

454.59 ± 19.75

236.58 ± 20.61

231.42 ± 19.18

3. Conclusions

45

56

57

From our structural modiﬁcation based on Dysodensiol K as lead

compound, the compounds 151 and 168 were identiﬁed as the potential

candidates drug for treatment of RA. Compounds 151 and 168 showed

ideal inhibitory activities in vitro against rat synovial cells generation. At

the same time, compounds 151 and 168 exhibited low cytotoxicity and

acute toxicity. In addition, we have demonstrated that, the compounds

151 and 168 can act as in vivo therapeutic agents and can show efﬁcacy

in the treatment of rheumatoid arthritis, at the same therapeutic level as

methotrexate in the CIA rat model. Compounds 151 and 168 can inhibit

the production of IL-6 factor and appropriately reduce the production of

63

64

66

67

75

78

151

156

166

168

169

171

177

178

195

methotrexate^b

DMSO

Normal

TNF-α factor during in vivo treatment. In the molecular docking studies

have found that compounds 151 and 168 have a good afﬁnity for the

receptor TLR4 associated with RA. In general, compounds 151 and 168

have satisfactory efﬁcacy as oral anti-rheumatoid arthritis agents. These

ﬁnding suggest the compounds 151 and 168 may be a candidates drug

for treatment of RA.

—

a

b

Values are the average of 3 independent experiments run in triplicate.

Methotrexate is use as positive control.

4. Experimental section

4.1. Chemistry

Arg262, compound 156 form tow H-bonds with Thr319 and Lys362 and

compound 169 form only one H-bond with Tyr292. Furthermore, the

total score (-log (K_D)) of the optimal conformation of compound 168 was

calculated to be 6.91. Additionally, the binding modes indicate that the

hydrophilic interactions between the host and guest molecules are

All commercially available reagents were purchased from Aladdin

(Shanghai, China) and solvents were purchased from Chronchem

(Chengdu, China), and when used without further puriﬁcation. In

Fig. 3. The rats paw volume.

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S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Fig. 4. The rats paw. a) normal group; b) blank group; c) methotrexate group; d) compound 151 group; e) compound 156 group; f) compound 168 group; g)

compound 169 group.

Fig. 5. The IL-6 and TNF-α concentrations.

reaction was completed, the mixture was distillation under reduced

pressure, removed of reaction solvent benzene, and to obtain crude

product ethyl 2-(2-methyl-1, 3-dioxolan-2-yl) acetate (compound 2a).

The crude product was puriﬁed to use silica gel column chromatography

(petroleum ether: ethyl acetate, 3:1). Removed solvents in vacuum

provided and to give the pure product compound 2a as a colorless liquid

(98.6% yield). The general method were used to synthesis ethyl 3-(2-

methyl-1, 3-dioxolan-2-yl) propanoate (compounds 2b) as was of yellow

oily liquid (98.9% yield).

Table 3

The LD₅₀test of results.

Compounds

Administration

LD₅₀(mg/kg)^a± SD

151

ig

2530.49 ± 8.60

2490.36 ± 7.65

2614.26 ± 9.19

2593.35 ± 8.33

1368.43 ± 5.34

156

168

169

methotrexate^b

a

Values are the average of 1 independent experiments run in triplicate.

Methotrexate is use as positive control.

b

4.1.2. Synthesis of compounds 3–40 and 79–138

A ethyl 2-(2-methyl-1, 3-dioxolan-2-yl) acetate (compound 2a,

17.42 g, 100 mmol) and cyclohexanone (9.81 g, 100 mmol) were dis-

solved in 100 mL of anhydrous ethyl alcohol was placed in a 250 mL

round-bottom ﬂask. The sodium ethanolate (CH₃CH₂ONa, 6.81 g, 100

mmol) used as an alkaline substancea for the reaction were added. After

the reactants were added, the reaction mixture was lasted for 12 h under

reﬂuxing with magnetic stirring. When the reﬂuxing reaction was

completed, the mixture was distillation under reduced pressure,

removed of reaction solvent ethyl alcohol. The residue mixture was

dissolved in 50 mL hydrochloric acid solution (2 mol.L^-1) and constant

temperature at 60℃ for 2 h with magnetic stirring. After the hydrolysis

reaction was completed, it was cooled, extracted with 40 mL ethyl ac-

etate three times and washed with 40 mL saturated sodium bicarbonate

(NaHCO₃). The combined organic layers were dried with anhydrous

sodium sulfate (Na₂SO₄), then ﬁltered and the ﬁltrate was collected. The

ﬁltrate was reduced pressure and evaporated to dry, and to obtain crude

product 1-(2-oxocyclohexyl)butane-1, 3-dione (compound 3). The crude

product was puriﬁed to use silica gel column chromatography (petro-

leum ether: ethyl acetate, 4:1). Removed solvents in vacuum provided

and to give the pure product compound 3 as a colorless liquid (89.2%

general, all reactions were performed under normal atmosphere and at

room temperature unless otherwise noted. All reactions were monitored

for completion by TLC using merck silica gel 60 F254 glass plates. Spots

were detected by viewing under UV lamps at 254 nm. ¹H NMR spectra

were recorded on Bruker NMR spectrometers at 400 MHz and ¹³C NMR

spectra were recorded on Bruker NMR spectrometers at 100 MHz,

respectively, tetramethylsilane (TMS) was used as internal standard.

Chemical shifts were signiﬁed in ppm relative to internal TMS in

DMSO‑d₆. The purity of the tested compounds was determined using an

Agilent 1260 series HPLC system with a C18 column, and that for all the

compounds was found to be greater than 95%.

4.1.1. Synthesis of compounds 2a-2b

A ethanediol (7.45 g, 120 mmol) and ethyl acetoacetate (compound

1a, 13.01 g, 100 mmol) were dissolved in 100 mL of anhydrous benzene

was placed in a 250 mL round-bottom ﬂask. The p-methylbenzene sul-

fonic acid (p-TsOH, 0.5% mol) used as a catalyst for the reaction were

added. After the reactants were added, the reaction mixture was lasted

for 48 h under reﬂuxing with magnetic stirring. When the reﬂuxing

10

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Fig. 6. Binding modes between TLR4 and representative active compounds. (a) The overall structure of TLR4-MD2 dimer in complex with co-crystalized antagonist

Eritoran (PDB ID: 3FXI). Putative binding pocket in TLR4 are shown as orange surfaces. Protein contact potential and hydrophobic lipophilic potential distrubutions

are shown in red/blue and cyan/brown surfaces, respectively. The binding modes of compound 151 (b), compound 156 (c), compound 168 (d) and compound 169

(e) with the TLR4-MD-2 complex. Residues around binding site with 5 Å are shown as blue stick. Hydrogen bonds interactions are represented as black dotted lines.

(For interpretation of the references to colour in this ﬁgure legend, the reader is referred to the web version of this article.)

yield). The general method were used to synthesis compounds 4–40 and

79–138 as was of yellow oily liquid.

mmol) anhydrous potassium hydroxide (KOH, 5.61 g, 100 mmol) were

dissolved in 100 mL of anhydrous ethyl alcohol was placed in a 250 mL

round-bottom ﬂask. After the reactants were added, the reaction mixture

was lasted for 12 h under reﬂuxing with magnetic stirring. When the

reﬂuxing reaction was completed, the mixture was distillation under

4.1.3. Synthesis of compounds 41–78 and 139–198

A 1-(2-oxocyclohexyl)butane-1, 3-dione (compound 3, 19.62 g, 100

11

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

reduced pressure, removed of reaction solvent ethyl alcohol. The residue

mixture was dissolved in 50 mL of deionized water, then adjust pH to

neutral with 2 mol.L^-1hydrochloric acid solution. After the extracted

with 40 mL ethyl acetate three times and washed with 40 mL saturated

sodium bicarbonate (NaHCO₃). The combined organic layers were dried

with anhydrous sodium sulfate (Na₂SO₄), then ﬁltered and the ﬁltrate

was collected. The ﬁltrate was reduced pressure and evaporated to dry,

and to obtain crude product compound 41. The crude product was pu-

riﬁed to use silica gel column chromatography (petroleum ether: ethyl

acetate, 4:1). Removed solvents in vacuum provided and to give the pure

product compound 41 as a colorless liquid (82.1% yield). The general

method were used to synthesis compounds 42–78 and 139–198 as was

of yellow oily liquid.

13.7, 7.0, 5.1, 1.8 Hz), 1.85 (dddd, J = 13.7, 9.6, 7.5, 6.9 Hz)), 2.00 (1H,

ddt, J = 8.1, 3.9, 2.7 Hz), 2.19–2.29 (2H, 2.22 (d, J = 16.2 Hz), 2.27 (d,

J = 16.2 Hz)), 2.66 (1H, d, J = 16.2 Hz), 4.05 (2H, dd, J = 9.6, 5.1 Hz);

¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.4, 14.5, 25.2, 31.6, 32.4, 34.1,

49.5, 52.7, 60.2, 126.8, 170.7, 206.3, 209.1; HR-ESI-MS m/z: calcd for

C₁₃H₁₈O₂{[M + H]⁺} 206.2850, found 206.1035; Anal. calcd for

C₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.65; H, 8.82; O,

15.53%.

compound 47, yellow oily liquid, yield 54.7%,; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 6.5 Hz), 1.14 (3H, d, J = 6.9 Hz), 1.64–1.71

(2H, 1.66 (dq, J = 6.9, 6.5 Hz), 1.69 (dq, J = 6.9, 6.5 Hz)), 1.82 (1H,

dddd, J = 13.1, 8.1, 6.9, 1.8 Hz), 2.01 (1H, dddd, J = 13.1, 7.5, 7.0, 3.9

Hz), 2.17–2.31 (2H, 2.20 (dddd, J = 13.7, 7.0, 5.1, 1.8 Hz), 2.26 (dddd,

J = 13.7, 9.6, 7.5, 6.9 Hz)), 2.48 (2H, ddd, J = 8.1, 3.9, 2.4 Hz), 2.74

(1H, d, J = 16.2 Hz), 4.06 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 11.2, 14.3, 19.1, 31.3, 32.3, 37.8, 56.6, 60.2, 60.3, 145.8,

170.7, 192.9, 211.6; HR-ESI-MS m/z: calcd for C₁₃H₁₈O₂{[M + H]⁺}

206.2850, found 206.1030; Anal. calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80;

O, 15.51; found: C, 75.64; H, 8.83; O, 15.54%.

compound 41, yellow oily liquid, yield 82.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.16–1.1.26 (2H, 1.16 (ddddd, J = 11.7, 8.1, 7.6, 7.0, 4.0

Hz), 1.23 (ddddd, J = 11.7, 8.1, 6.9, 4.3, 1.8 Hz)), 1.85–1.92 (2H, 1.88

(dddd, J = 13.2, 8.1, 6.6, 4.0 Hz), 1.91 (dddd, J = 13.2, 8.1, 8.0, 4.3

Hz)), 2.46 (2H, ddd, J = 13.9, 7.0, 1.8 Hz), 2.72 (1H, d, J = 15.9 Hz),

4.04 (2H, dd, J = 8.0, 6.6 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.1,

27.1, 34.0, 51.1, 60.0,128.0, 156.7, 20.5.5, 208.9; HR-ESI-MS m/z: calcd

for C₉H₁₀O₂{[M + H]⁺} 150.1770, found 150.1124; Anal. calcd for

C₉H₁₀O₂: C, 71.98; H, 6.71; O, 21.31; found: C, 71.96; H, 6.72; O,

21.32%.

compound 48, yellow oily liquid, yield 46.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (9H, s), 1.13–1.21 (2H, 1.16 (dddd, J = 13.0, 7.5, 7.0,

3.9 Hz), 1.18 (dddd, J = 13.0, 8.1, 6.9, 1.8 Hz)), 1.64 (2H, dddd, J =

13.7, 7.0, 5.1, 1.8 Hz), 1.81 (2H, dd, J = 8.1, 3.9 Hz), 2.19–2.29 (2H,

2.20 (d, J = 16.2 Hz), 2.28 (d, J = 16.2 Hz)), 2.71 (1H, dd, J = 13.7, 9.6

Hz), 4.05 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ:

14.3, 27.0, 27.1, 41.3, 54.9, 56.2, 60.2, 128.2, 156.2, 194.9, 206.1; HR-

ESI-MS m/z: calcd for C₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.1028;

Anal. calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.65; H,

8.83; O, 15.52%.

compound 42, yellow oily liquid, yield 73.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.20 (3H, d, J = 6.7 Hz), 1.41–1.43 (2H, 1.41 (dddd, J =

13.2, 7.0, 5.1, 1.8 Hz), 1.43(dddd, J = 13.2, 9.6, 7.5, 6.9 Hz)), 2.21 (1H,

dqd, J = 8.1, 6.7, 3.9 Hz), 2.63–2.76 (2H, 2.63 (d, J = 16.2 Hz), 2.66 (d,

J = 16.2 Hz), 3.90 (1H, dd, J = 8.0 Hz), 4.10 (2H, dd, J = 9.6, 5.1 Hz);

¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.6, 20.1, 32.5, 34.1, 48.9, 59.8,

128.2, 169.1, 194.7, 206.4; HR-ESI-MS m/z: calcd for C₁₀H₁₂O₂{[M +

H]⁺}164.2040, found 164.1144; Anal. calcd for C₁₀H₁₂O₂: C, 73.15; H,

7.37; O, 19.49; found: C, 73.10; H, 7.39; O, 19.51%.

compound 49, yellow oily liquid, yield 50.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.84 (3H, t, J = 6.5 Hz), 1.17–1.28 (4H, 1.25 (tt, J = 7.6,

6.5 Hz), 1.28 (h, J = 6.5 Hz)), 1.61–1.67 (2H, 1.62 (h, J = 6.5 Hz), 1.67

(tt, J = 7.6, 6.5 Hz)), 1.82 (2H, dddd, J = 13.7, 7.0, 5.1, 1.8 Hz), 2.02

(1H, ddt, J = 8.1, 3.9, 2.7 Hz), 2.19–2.30 (2H, 2.22 (d, J = 16.2 Hz),

2.29 (d, J = 16.2 Hz)), 2.50 (2H, dd, J = 13.4, 8.1 Hz) 2.67 (1H, td, J =

7.6, 2.7 Hz), 4.05 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 14.3, 14.5, 22.6, 27.0, 32.2, 32.4, 34.1, 49.5, 52.6, 60.3,

126.7, 170.7, 195.7, 206.2; HR-ESI-MS m/z: calcd for C₁₄H₂₀O₂[M +

H]⁺220.3120, found 220.0936; Anal. calcd for C₁₄H₂₀O₂: C, 76.33; H,

9.15; O, 14.52; found: C, 76.30; H, 9.16; O, 14.54%.

compound 43, yellow oily liquid, yield 72.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.05 (3H, t, J = 6.9 Hz), 1.16–1.21 (2H, 1.16 (dddd, J =

13.3, 8.1, 6.9, 1.8 Hz), 1.20 (dd, J = 6.9, 2.7 Hz)), 1.42 (2H, qd, J = 6.9,

2.7 Hz), 2.00 (1H, dddd, J = 13.7, 7.0, 5.1, 1.8 Hz), 2.09 (2H, ddt, J =

8.1, 3.9, 2.7 Hz), 3.88 (1H, d, J = 16.2 Hz), 4.07 (2H, dd, J = 9.6, 5.1

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.6, 17.9, 23.8, 32.7, 34.0, 52.7,

53.9, 55.6, 128.2, 170.6, 206.5, 207.3; HR-ESI-MS m/z: calcd for

C

₁₁H₁₄O₂{[M + H]⁺}178.2310, found 178.0536; Anal. calcd for

₁₁H₁₄O₂: C, 74.13; H, 7.92; O, 17.95; found: C, 74.10; H, 7.92; O,

compound 50, yellow oily liquid, yield 46.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.87 (3H, t, J = 7.0 Hz), 1.17–1.26 (4H, 1.17 (h, J = 7.0

Hz), 1.26 (h, J = 7.0 Hz)), 1.64 (2H, tt, J = 7.0, 6.9 Hz), 1.83–1.88 (4H,

1.83 (tt, J = 7.0, 6.9 Hz), 1.85 (td, J = 7.5, 2.7 Hz)), 2.00 (1H, ddt, J =

8.1, 3.9, 2.7 Hz), 2.20–2.31 (4H, 2.22 (dddd, J = 13.4, 8.1, 6.9, 1.8 Hz),

2.28 (td, J = 7.5, 2.7 Hz)), 2.48 (2H, d, J = 16.2 Hz), 2.67 (1H, d, J =

16.2 Hz), 4.06 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 14.1, 20.8, 22.8, 27.7, 27.8, 29.4, 29.8, 29.9, 32.0, 37.7, 48.7, 52.1,

128.2, 160.2, 205.1, 206.2; HR-ESI-MS m/z: calcd for C₁₆H₂₄O₂{[M +

H]⁺}248.3660, found 248.1846; Anal. calcd for C₁₆H₂₄O₂: C, 77.38; H,

9.74; O, 12.88; found: C, 77.34; H, 9.75; O, 12.89%.

17.96%.

compound 44, yellow oily liquid, yield 66.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.5 Hz), 1.14–1.25 (4H, 1.32 (tq, J = 6.6,

6.5 Hz), 1.32 (tq, J = 6.6, 6.5 Hz)), 2.00 (1H, dddd, J = 13.4, 7.5, 7.0,

3.9 Hz), 2.12 (2H, dddd, J = 13.7, 7.0, 5.1, 1.8 Hz, 2.46 (1H, ddt, J =

8.1, 3.9, 2.8 Hz), 2.72 (2H, d, J = 16.2 Hz), 4.06 (1H, dd, J = 9.6, 5.1

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.6, 16.8, 27.0, 36.5, 48.9, 53.0,

59.9, 126.2, 169.1, 194.6, 206.3; HR-ESI-MS m/z: calcd for

C₁₂H₁₆O₂{[M + H]⁺}192.2580, found 192.1013; Anal. calcd for

C

₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found: C, 74.94; H, 8.39; O,

16.67%.

compound 51, yellow oily liquid, yield 46.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (2H, t, J = 7.0 Hz), 1.16–1.24 (2H, 1.19 (h, J = 7.0

Hz), 1.24 (h, J = 7.0 Hz)), 1.58–1.71 (4H, 1.64 (tt, J = 7.0, 6.9 Hz), 1.70

(tt, J = 7.0, 6.9 Hz)), 1.84 (1H, tt, J = 7.5, 6.5 Hz), 2.14–2.30 (4H, 2.19

(tt, J = 7.5, 6.5 Hz), 2.29 (tt, J = 6.9, 6.5 Hz)), 2.47 (1H, tt, J = 6.9, 6.5

compound 45, yellow oily liquid, yield 65.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (6H, 0.88, d, J = 6.9 Hz), 1.15–1.31 (4H, 1.17 (dddd,

J = 13.1, 8.1, 6.9, 1.8 Hz), 1.22 (dddd, J = 13.1, 7.5, 7.0, 3.9 Hz)), 1.68

(1H, dddd, J = 13.7, 7.0, 5.1, 1.8 Hz), 2.02 (1H, tq, J = 6.9, 2.4 Hz),

2.20–2.35 (2H, 2.23 (ddd, J = 8.1, 3.9, 2.4 Hz), 2.32 (d, J = 16.2 Hz)),

4.08 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 19.4,

20.1, 27.0, 32.2, 52.7, 55.4, 56.2, 128.2, 169.1, 194.7, 206.3; HR-ESI-

MS m/z: calcd for C₁₂H₁₆O₂{[M + H]⁺}192.2580, found 192.1460;

Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found: C, 74.92; H,

8.41; O, 16.66%.

Hz), 2.68 (1H, td, J = 7.5, 2.7 Hz), 4.02 (2H, dd, J = 9.6, 5.1 Hz); ¹³

C

NMR (100 MHz, DMSO‑d₆) δ: 20.7, 24.9, 25.3, 27.7, 29.7, 30.9, 38.4,

52.7, 127.0, 174.3, 203.4, 209.0; HR-ESI-MS m/z: calcd for C₁₄H₁₈O₂

{[M + H]⁺}218.2960, found 218.1618; Anal. calcd for C₁₄H₁₈O₂: C,

77.03; H, 8.31; O, 14.66; found: C, 77.05; H, 8.33; O, 14.60%.

compound 52, yellow oily liquid, yield 45.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (2H, dtt, J = 12.8, 10.3, 2.8 Hz), 1.04–1.14 (4H, 1.07

(dtd, J = 12.6, 10.3, 2.8 Hz), 1.14 (dtd, J = 12.6, 10.3, 2.8 Hz)), 1.25

(1H, ddd, J = 10.3, 8.1, 3.9 Hz), 1.57–1.71 (2H, 1.60 (dq, J = 12.6, 2.8

Hz), 1.70 (dt, J = 12.0, 2.8 Hz)), 1.73–1.88 (1H, dtt, J = 12.0, 10.3, 2.8

compound 46, yellow oily liquid, yield 60.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.84 (3H, t, J = 6.5 Hz), 1.17–1.27 (4H, 1.19 (tt, J = 7.6,

6.5 Hz), 1.25 (h, J = 6.5 Hz)), 1.61–1.69 (2H, 1.62 (dddd, J = 13.4, 8.1,

6.9, 1.8 Hz), 1.67 (td, J = 7.6, 2.7 Hz)), 1.81–1.87 (2H, 1.82 (dddd, J =

12

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

Hz), 2.14–2.30 (4H, 2.20 (dt, J = 12.8, 2.8 Hz), 2.30 (dt, J = 12.8, 2.8

Hz)), 2.52 (1H, d, J = 16.2 Hz), 2.64–2.76 (2H, 2.64 (dtt, J = 12.8, 10.3,

2.8 Hz), 2.74 (dq, J = 12.6, 2.8 Hz)), 4.05 (2H, dd, J = 9.6, 5.1 Hz); ¹³C

NMR (100 MHz, DMSO‑d₆) δ: 14.6, 19.1, 25.9, 33.9, 35.9, 45.2, 53.2,

57.9, 58.9, 127.4, 169.2, 197.5, 208.3; HR-ESI-MS m/z: calcd for

C₁₅H₂₀O₂{[M + H]⁺} 232.3230, found 232.1096; Anal. calcd for

compound 59, yellow oily liquid, yield 45.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (3H, d, J = 6.6 Hz), 1.76–1.90 (2H, 1.79 (ddd, J =

18.2, 7.3, 3.9 Hz), 1.90 (ddd, J = 18.2, 8.1, 7.0 Hz)), 2.27 (1H, dqd, J =

8.1, 6.6, 3.9 Hz), 2.65 (1H, d, J = 16.3 Hz), 4.05 (2H, dd, J = 7.3, 7.0

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.7, 26.9, 32.3, 46.1, 62.2,

144.1, 150.1, 195.7, 202.5, 202.7; HR-ESI-MS m/z: calcd for C₁₀H₁₀O₃

{[M + H]⁺} 178.1870, found 178.0096; Anal. calcd for C₁₀H₁₀O₃: C,

67.41; H, 5.66; O, 26.94; found: C, 67.37; H, 5.65; O, 26.98%.

C

₁₅H₂₀O₂: C, 77.55; H, 8.68; O, 13.77; found: C, 77.50; H, 8.69; O,

13.78%.

compound 53, yellow oily liquid, yield 50.6%; ¹H NMR (400 MHz,

compound 60, yellow oily liquid, yield 84.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.11.09–1.28 (2H, 1.17 (ddddd, J = 12.9, 7.3, 5.4, 1.9, 1.4

Hz), 1.25 (ddtd, J = 12.9, 9.3, 7.1, 5.6 Hz)), 2.00 (1H, dddd, J = 13.3,

5.6, 5.1, 1.4 Hz), 2.12 (2H, dddd, J = 13.3, 9.6, 9.3, 5.4 Hz), 2.43–2.55

(2H, 2.45 (ddd, J = 17.1, 6.1, 1.4 Hz), 2.54 (ddd, J = 12.0, 7.3, 7.1 Hz)),

2.67–2.74 (2H, 2.69 (ddd, J = 14.9, 8.5, 6.1 Hz), 2.73 (ddd, J = 17.1,

8.5, 6.0 Hz), 4.05 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 14.1, 25.4, 30.9, 37.6, 41.7, 56.4, 126.2, 157.1, 205.9,

207.9; HR-ESI-MS m/z: calcd for C₁₀H₁₂O₂{[M + H]⁺}164.2040, found

164.0071; Anal. calcd for C₁₀H₁₂O₂: C, 73.15; H, 7.37; O, 19.49; found:

C, 73.12; H, 7.38; O, 19.51%.

DMSO‑d₆) δ: 1.08–1.25 (2H, 1.18 (dddd, J = 13.5, 8.1, 6.9, 1.8 Hz), 1.22

(dddd, J = 13.5, 7.5, 7.0, 3.9 Hz)), 1.45–1.66 (2H, 1.51 (dddd, J = 13.7,

7.0, 5.1, 1.8 Hz), 1.63 (dddd, J = 13.7, 9.6, 7.5, 6.9 Hz)), 2.25 (1H, d, J

= 16.2 Hz), 3.39 (1H, d, J = 16.2 Hz), 4.06 (2H, dddd, J = 7.8, 7.7, 1.9,

0.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 17.6, 21.9, 55.2, 58.1, 58.9,

112.1, 114.7, 124.2, 130.9, 146.0, 169.4, 202.3, 209.6; HR-ESI-MS m/z:

calcd for C₁₅H₁₄O₂{[M + H]⁺} 226.2750, found 226.1056; Anal. calcd

for C₁₅H₁₄O₂: C, 79.62; H, 6.24; O, 14.14; found: C, 79.58; H, 6.26; O,

14.17%.

compound 54, yellow oily liquid, yield 60.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.14–1.18 (2H, 1.16 (dddd, J = 15.9, 7.5, 7.0, 3.9 Hz), 1.18

(dddd, J = 12.8, 9.6, 7.5, 6.9 Hz), 1.52 (3H, s), 1.92 (1H, dddd, J = 12.8,

7.0, 5.1, 1.8 Hz), 2.00 (1H, d, J = 16.2 Hz), 2.19–2.32 (2H, 2.20 (d, J =

16.2 Hz), 2.29 (dd, J = 8.1, 3.9 Hz)), 4.04 (dd, J = 9.6, 5.1 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 14.3, 24.4, 51.3, 56.6, 60.0, 60.2, 126.0, 169.0,

172.9, 201.4, 206.6; HR-ESI-MS m/z: calcd for C₁₁H₁₂O₄{[M + H]⁺}

208.21300, found 208.1332; Anal. calcd for C₁₁H₁₂O₄: C, 63.45; H,

5.81; O, 30.74; found: C, 63.40; H, 5.83; O, 30.76%.

compound 61, yellow oily liquid, yield 76.0%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.01 (3H, d, J = 6.6 Hz), 1.62–1.81 (2H, 1.6.2 (dddd, J =

13.5, 5.4, 1.9, 1.4 Hz), 1.71 (dddd, J = 13.5, 9.3, 7.1, 5.6 Hz)), 2.01 (1H,

dddd, J = 13.2, 5.6, 5.1, 1.4 Hz), 2.11–2.33 (2H, 2.17 (dddd, J = 13.2,

9.6, 9.3, 5.4 Hz), 2.27 (ddd, J = 17.1, 6.1, 1.4 Hz)), 2.56 (1H, ddd, J =

14.9, 8.5, 6.1 Hz), 2.70–2.76 (2H, 2.70 (dqd, J = 7.1, 6.6, 1.9 Hz), 2.75

(ddd, J = 17.1, 8.5, 6.0 Hz)), 4.06 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 15.0, 17.9, 32.2, 34.8, 38.3, 39.6, 52.7, 127.4,

162.2, 206.0, 207.6; HR-ESI-MS m/z: calcd for C₁₁H₁₄O₂{[M + H]⁺}

178.2310, found 178.1429; Anal. calcd for C₁₁H₁₄O₂: C, 74.13; H, 7.92;

O, 17.95; found: C, 74.10; H, 7.93; O, 17.97%.

compound 55, yellow oily liquid, yield 56.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.17 (3H, t, J = 7.1 Hz), 1.50–1.57 (2H, 1.51 (dddd, J =

15.9, 7.5, 7.0, 3.9 Hz), 1.57 (dddd, J = 12.8, 9.6, 7.5, 6.9 Hz)), 1.90 (1H,

dddd, J = 12.8, 7.0, 5.1, 1.8 Hz), 1.98 (1H, d, J = 16.2 Hz), 2.19–2.30

(2H, 2.21 (d, J = 16.2 Hz), 2.30 (dd, J = 8.1, 3.9 Hz)), 3.99–4.08 (4H,

3.99 (q, J = 7.1 Hz), 4.08 (q, J = 7.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 13.9, 20.5, 24.3, 30.5, 56.8, 59.9, 64.3, 125.5, 170.5, 172.9, 203.8,

209.8; HR-ESI-MS m/z: calcd for C₁₂H₁₄O₄{[M + H]⁺} 222.2400, found

222.0518; Anal. calcd for C₁₂H₁₄O₄: C, 64.85; H, 6.35; O, 28.80; found:

C, 64.80; H, 6.36; O, 28.81%.

compound 62, yellow oily liquid, yield 74.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.9 Hz), 1.12–1.31 (2H, 1.19 (dddd, J =

13.0, 5.4, 1.9, 1.4 Hz), 1.26 (qd, J = 6.9, 2.8 Hz)), 1.58–1.68 (2H, 1.60

(qd, J = 6.9, 2.8 Hz), 1.65 (dddd, J = 13.0, 9.3, 7.1, 5.6 Hz)), 1.84 (1H,

2.14 dddd, J = 13.2, 5.6, 5.1, 1.4 Hz), 2.18–2.27 (2H, 2.11 (dddd, J =

13.2, 9.6, 9.3, 5.4 Hz), 2.25 (ddd, J = 17.9, 6.1, 1.4 Hz)), 2.47 (1H, ddd,

J = 14.9, 8.5, 6.1 Hz), 2.64–2.76 (2H, 2.65 (dtd, J = 7.1, 2.8, 1.9 Hz),

2.74 (ddd, J = 17.9, 8.5, 6.0 Hz)), 4.05 (2H, dd, J = 9.6, 5.1 Hz); ¹³C

NMR (100 MHz, DMSO‑d₆) δ: 14.6, 17.9, 32.2, 36.5, 38.3, 39.6, 51.8,

56.9, 127.9, 161.1, 201.6, 207.3; HR-ESI-MS m/z: calcd for

compound 56, yellow oily liquid, yield 59.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.13–1.20 (2H, 1.13 (dddd, J = 15.6, 7.5, 7.0, 3.9 Hz), 1.20

(dddd, J = 12.8, 9.6, 7.5, 6.9 Hz)), 1.43 (2H, dddd, J = 12.8, 7.0, 5.1,

1.8 Hz), 2.08 (3H, s), 2.19 (1H, dddd, J = 15.6, 8.1, 6.9, 1.8 Hz)), 2.66

(1H, d, J = 16.2 Hz), 4.04 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 14.2, 23.1, 24.4, 29.5, 33.8, 42.7, 59.9, 128.0, 170.2,

172.7, 205.6, 207.4; HR-ESI-MS m/z: calcd for C₁₁H₁₂O₃{[M + H]⁺}

192.2140, found 192.0210; Anal. calcd for C₁₁H₁₂O₃: C, 68.74; H, 6.29;

O, 24.97; found: C, 68.70; H, 6.29; O, 24.99%.

C

₁₂H₁₆O₂{[M + H]⁺}192.2580, found 192.1063; Anal. calcd for

₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found: C, 74.93; H, 8.40; O,

16.68%.

compound 63, yellow oily liquid, yield 68.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.87 (3H, t, J = 6.5 Hz), 1.14–1.22 (6H, 1.14 (tq, J = 6.6,

6.5 Hz), 1.17 (tq, J = 6.6, 6.5 Hz), 1.19 (dddd, J = 13.0, 5.4, 1.9, 1.4 Hz),

1.22 (dddd, J = 13.0, 9.3, 7.1, 5.6 Hz)), 2.00 (1H, ddd, J = 17.9, 6.1, 1.4

Hz), 2.12 (1H, dtd, J = 7.1, 2.8, 1.9 Hz), 2.46 (2H, ddd, J = 14.9, 8.5,

6.1 Hz), 2.72 (2H, ddd, J = 17.9, 8.5, 6.0 Hz), 4.06 (2H, dd, J = 9.6, 5.1

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.4, 18.9, 21.1, 32.5, 35.7, 36.6,

38.0, 46.4, 60.2, 125.5, 170.8, 207.4, 209.8; HR-ESI-MS m/z: calcd for

compound 57, yellow oily liquid, yield 39.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.07–1.27 (2H, 1.08 (dddd, J = 13.8, 8.1, 6.9, 1.8 Hz), 1.26

(dddd, J = 12.8, 9.6, 7.5, 6.9 Hz)), 1.47 (1H, dddd, J = 13.8, 7.5, 7.0,

3.9 Hz), 1.63–1.76 (2H, 1.68 (dddd, J = 12.8, 7.0, 5.1, 1.8 Hz), 1.73 (d,

J = 16.2 Hz), 3.36 (1H, d, J = 16.2 Hz), 4.44 (2H, dd, J = 9.6, 5.1 Hz);

¹³C NMR (100 MHz, DMSO‑d₆) δ: 17.3, 29.5, 36.5, 50.0, 59.4, 128.1,

174.5, 202.9, 206.1; HR-ESI-MS m/z: calcd for C₉H₉ClO₂{[M + H]⁺}

184.6190, found 184.0661; Anal. calcd for C₉H₉ClO₂: C, 58.55; H, 4.91;

Cl, 19.20; O, 17.33; found: C, 58.50; H, 4.93; Cl, 19.26; O, 17.30%.

compound 58, yellow oily liquid, yield 53.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 6.5 Hz), 1.14–1.34 (4H, 1.18 (tt, J = 6.7,

6.5 Hz), 1.25 (h, J = 6.5 Hz)), 1.37–1.50 (4H, 1.39 (h, J = 6.5 Hz), 1.49

(dt, J = 6.5 Hz)), 1.82 (1H, td, J = 6.7, 3.7 Hz), 2.00 (1H, td, J = 6.7, 3.7

Hz), 2.04–2.30 (4H, 2.08 (ddd, J = 13.8, 5.1, 1.8 Hz), 2.25 (ddd, J =

13.8, 9.6, 6.9 Hz)), 2.52 (2H, d, J = 6.6 Hz), 3.41 (3H, s), 4.05 (2H, dd, J

= 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.4, 22.5, 27.2, 27.7,

32.1, 38.1, 39.1, 50.9, 52.3, 53.8, 55.2, 60.2, 130.6, 172.5, 174.0, 207.1,

219.7; HR-ESI-MS m/z: calcd for C₁₇H₂₄O₄{[M + H]⁺} 292.3750, found

292.1035; Anal. calcd for C₁₇H₂₄O₄: C, 69.84; H, 8.27; O, 21.89; found:

C, 69.81; H, 8.29; O, 21.88%.

C

₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.1050; Anal. calcd for

₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.64; H, 8.83; O,

15.53%.

compound 64, yellow oily liquid, yield 67.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.14–1.22 (6H, 1.17 (d, J = 6.9 Hz), 1.17(d, J = 6.9 Hz)),

1.80 (1H, dddd, J = 13.2, 9.3, 7.1, 5.6 Hz), 1.90 (1H, ddd, J = 17.9, 6.1,

1.4 Hz), 1.98 (1H, dddd, J = 13.2, 5.4, 1.9, 1.4 Hz), 2.09 (2H, dddd, J =

13.5, 5.6, 5.1, 1.4 Hz), 2.33–2.41 (2H, 2.36 (dd, J = 6.9, 2.4 Hz), 2.39

(dddd, J = 13.5, 9.6, 9.3, 5.4 Hz)), 2.63–2.68 (2H, 2.63 (ddd, J = 14.9,

8.5, 6.1 Hz), 2.68 (ddd, J = 7.1, 2.4, 1.9 Hz)), 4.03 (2H, dd, J = 9.6, 5.1

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 13.9, 22.3, 28.0, 29.5, 32.0, 37.9,

57.5, 60.2, 122.6, 174.3, 205.6, 207.4; HR-ESI-MS m/z: calcd for

C

₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.1617; Anal. calcd for

₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.63; H, 8.83; O,

15.54%.

13

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

compound 65, yellow oily liquid, yield 62.1%; ¹H NMR (400 MHz,

219.3; HR-ESI-MS m/z: calcd for C₁₅H₂₀O₂{[M + H]⁺} 232.3230, found

232.1411; Anal. calcd for C₁₅H₂₀O₂: C, 77.55; H, 8.68; O, 13.77; found:

C, 77.50; H, 8.69; O, 13.79%.

DMSO‑d₆) δ: 0.89 (3H, t, J = 6.5 Hz), 1.13–1.21 (8H, 1.13 (tt, J = 7.6,

6.5 Hz), 1.16 (h, J = 6.5 Hz), 1.19 (tt, J = 7.6, 6.5 Hz), 1.21 (tt, J = 7.6,

6.5 Hz)), 2.00 (1H, dd, J = 5.4, 1.9 Hz), 2.12 (1H, ddd, J = 17.9, 6.1, 1.4

Hz), 2.40–2.48 (2H, 2.43 (dddd, J = 13.0, 9.3, 7.1, 5.6 Hz), 2.48 (td, J =

7.6, 2.8 Hz)), 2.72 (2H, dddd, J = 13.5, 5.6, 5.1, 1.4 Hz), 4.06 (2H, dd, J

= 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.4, 14.6, 25.2, 29.5,

31.6, 32.4, 34.1, 38.6, 49.5, 53.9, 126.8, 157.1, 206.3, 209.1; HR-ESI-

MS m/z: calcd for C₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1062;

Anal. calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.30; H,

9.15; O, 14.56%.

compound 71, yellow oily liquid, yield 47.0%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18–1.28 (2H, 1.23 (dtt, J = 12.8, 10.3, 2.8 Hz), 1.28

(dtd, J = 12.6, 10.3, 2.8 Hz)), 1.57–1.70 (4H, 1.61 (dtd, J = 12.6, 10.3,

2.8 Hz), 1.68 (dq, J = 12.6, 2.8 Hz)), 1.75–1.91 (5H, 1.81 (dd, J = 12.8,

2.8 Hz), 1.86 (dtt, J = 12.8, 10.3, 2.8 Hz)), 2.00 (1H, dq, J = 12.6, 2.8

Hz), 2.14–2.34 (3H, 2.14 (dddd, J = 13.5, 7.3, 5.4, 1.4 Hz), 2.19 (tdt, J

= 10.3, 10.1, 2.8 Hz), 2.26 (dddd, J = 13.4, 5.6, 5.1, 1.4 Hz)), 2.48 (2H,

dddd, J = 13.5, 9.3, 7.1, 5.6 Hz), 2.63–2.76 (2H, 2.65 (dddd, J = 13.4,

9.6, 9.3, 5.4 Hz), 2.12), 2.71 (ddd, J = 17.9, 6.1, 1.4 Hz)), 4.05 (2H, dd,

J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 19.5, 24.3, 25.9, 27.0,

31.7, 33.0, 35.5, 35.9, 45.2, 55.5, 58.9, 129.1, 169.2, 205.1, 208.1; HR-

ESI-MS m/z: calcd for C₁₆H₂₂O₂{[M + H]⁺} 246.3500, found 246.1486;

Anal. calcd for C₁₆H₂₂O₂: C, 78.01; H, 9.00; O, 12.99; found: C, 78.03; H,

9.01; O, 12.95%.

compound 66, yellow oily liquid, yield 56.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.04 (3H, t, J = 6.5 Hz), 1.16–1.22 (5H, 1.16 (d, J = 6.9

Hz), 1.20 (dq, J = 6.9, 6.5 Hz)), 1.32 (2H, dq, J = 6.9, 6.5 Hz), 1.92 (1H,

hd, J = 6.9, 2.4 Hz), 2.01 (1H, ddd, J = 17.9, 6.1, 1.4 Hz), 2.12 (1H, dd,

J = 13.2, 5.6 Hz), 2.26–2.43 (2H, 2.27 (dddd, J = 13.5, 5.6, 5.1, 1.4 Hz),

2.38 (dddd, J = 13.5, 9.6, 9.3, 5.4 Hz)), 2.68 (2H, ddd, J = 14.9, 8.5, 6.1

Hz), 4.04 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ:

11.2, 17.7, 19.1, 30.7, 31.3, 33.5, 37.8, 41.2, 56.6, 60.2, 125.6, 170.7,

204.2, 209.8; HR-ESI-MS m/z: calcd for C₁₄H₂₀O₂{[M + H]⁺}220.3120,

found 220.1056; Anal. calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52;

found: C, 76.31; H, 9.16; O, 14.54%.

compound 72, yellow oily liquid, yield 52.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.54–1.67 (2H, 1.55 (dddd, J = 13.7, 7.3, 5.4, 1.4 Hz), 1.63

(dddd, J = 13.7, 9.3, 7.1, 5.6 Hz)), 1.82 (2H, dddd, J = 13.5, 9.6, 9.3,

5.4 Hz), 1.99 (1H, ddd, J = 15.0, 8.5, 6.1 Hz), 2.23 (2H, dddd, J = 13.5,

5.6, 5.1, 1.4 Hz), 3.40 (1H, ddd, J = 17.9, 6.1, 1.4 Hz), 4.04 (2H, dd, J =

9.6, 5.1 Hz), 7.29–7.38 (3H, 7.31 (dddd, J = 7.8, 7.7, 1.9, 0.5 Hz), 7.35

(dddd, J = 7.8, 1.3, 1.2, 0.5 Hz)), 7.56 (2H, tt, J = 7.7, 1.3 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 13.1, 20.0, 31.1, 40.1, 58.1, 58.9, 124.1, 130.9,

144.2, 146.0, 149.0, 171.1, 208.5, 209.7; HR-ESI-MS m/z: calcd for

compound 67, yellow oily liquid, yield 49.0%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (9H, s), 1.17–1.33 (2H, 1.21 (dddd, J = 14.1, 5.4, 1.9,

1.4 Hz), 1.29 (dddd, J = 14.1, 9.3, 7.1, 5.6 Hz)), 1.84 (1H, ddd, J = 17.9,

6.1, 1.4 Hz), 1.90 (1H, dddd, J = 13.5, 5.6, 5.1, 1.4 Hz), 2.25 (2H, ddd, J

= 14.9, 8.5, 6.1 Hz), 2.89 (2H, ddd, J = 17.9, 8.5, 6.0 Hz), 4.06 (1H, dd,

J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.1, 27.0, 29.5, 32.4,

38.3, 47.4, 54.2, 60.2, 128.2, 170.8, 206.3, 208.9; HR-ESI-MS m/z: calcd

for C₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1050; Anal. calcd for

C

₁₆H₁₆O₂{[M + H]⁺} 240.3020, found 240.0926; Anal. calcd for

₁₆H₁₆O₂: C, 79.97; H, 6.71; O, 13.32; found: C, 79.92; H, 6.73; O,

13.35%.

compound 73, yellow oily liquid, yield 62.5%; ¹H NMR (400 MHz,

C

₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.30; H, 9.18; O,

DMSO‑d₆) δ: 1.48–1.57 (2H, 1.50 (dddd, J = 13.3, 9.3, 7.1, 5.6 Hz), 1.57

(dddd, J = 14.2, 5.6, 5.1, 1.4 Hz)), 1.99 (1H, dddd, J = 14.2, 9.6, 9.3,

5.4 Hz), 2.19–2.31 (2H, 2.21 (ddd, J = 14.9, 8.5, 6.1 Hz), 2.29 (ddd, J =

17.9, 8.5, 6.0 Hz)), 2.45 (2H, ddd, J = 17.9, 6.1, 1.4 Hz), 2.71 (1H, dd, J

= 7.3, 7.1 Hz), 3.65 (3H, s), 4.04 (2H, dd, J = 9.6, 5.1 Hz; ¹³C NMR (100

MHz, DMSO‑d₆) δ: 14.1, 20.6, 33.5, 37.6, 52.6, 56.7, 59.9, 125.8, 172.8,

174.7, 206.4, 209.8; HR-ESI-MS m/z: calcd for C₁₂H₁₄O₄{[M + H]⁺}

222.2400, found 220.1258; Anal. calcd for C₁₂H₁₄O₄: C, 64.85; H, 6.35;

O, 28.80; found: C, 64.80; H, 6.37; O, 28.82%.

14.51%.

compound 68, yellow oily liquid, yield 52.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.5 Hz), 1.17–1.35 (8H, 1.17 (tt, J = 7.5,

6.5 Hz), 1.23 (h, J = 6.5 Hz), 1.28 (h, J = 6.5 Hz), 1.30 (tt, J = 7.5, 6.5

Hz)), 1.53–1.67 (2H, 1.55 (dddd, J = 13.7, 7.3, 5.4, 1.4 Hz), 1.65 (td, J

= 7.5, 3.2 Hz)), 2.00 (1H, dddd, J = 13.4, 5.6, 5.1, 1.4 Hz), 2.25 (2H, td,

J = 7.5, 3.2 Hz), 2.49 (2H, dddd, J = 13.7, 9.3, 7.1, 5.6 Hz), 2.72 (2H,

dddd, J = 13.4, 9.6, 9.3, 5.4 Hz), 4.03 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 14.4, 17.3, 22.6, 27.0, 32.2, 32.4, 33.8, 34.1,

36.7, 49.5, 53.9, 128.2, 170.7, 206.3, 209.1; HR-ESI-MS m/z: calcd for

compound 74, yellow oily liquid, yield 58.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.17 (3H, t, J = 7.1 Hz), 1.51 (2H, dddd, J = 13.3, 7.3, 5.4,

1.4 Hz), 1.97 (1H, dddd, J = 14.2, 9.6, 9.3, 5.4 Hz), 2.18–2.30 (2H, 2.18

(dddd, J = 13.3, 9.3, 7.1, 5.6 Hz), 2.29 (dddd, J = 14.2, 5.6, 5.1, 1.4 Hz),

2.38 (2H, ddd, J = 17.9, 6.1, 1.4 Hz), 2.65 (1H, dd, J = 7.3, 7.1 Hz), 4.03

(2H, dd, J = 9.6, 5.1 Hz), 4.21 (2H, q, J = 7.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 14.0, 18.2, 20.6, 33.5, 37.6, 52.6, 56.7, 59.9, 125.8, 172.4,

174.7, 206.4,209.8; HR-ESI-MS m/z: calcd for C₁₃H₁₆O₄{[M + H]⁺}

236.2670, found 236.0953; Anal. calcd for C₁₃H₁₆O₄: C, 66.09; H, 6.83;

O, 27.09; found: C, 66.04; H, 6.88; O, 27.12%.

C

₁₅H₂₂O₂{[M + H]⁺}234.3390, found 234.1158; Anal. calcd for

₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found: C, 76.84; H, 9.48; O,

13.66%.

compound 69, yellow oily liquid, yield 49.7%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 7.0 Hz), 1.13–1.34 (10H, 1.14 (h, J = 6.5

Hz), 1.21 (h, J = 7.0 Hz), 1.25 (h, J = 7.0 Hz), 1.31 (tt, J = 7.0, 6.5 Hz)),

1.98 (1H, dddd, J = 13.4, 5.6, 5.1, 1.4 Hz), 2.13 (1H, tt, J = 7.0, 6.5 Hz),

2.24 (2H, dddd, J = 13.7, 7.3, 5.4, 1.4 Hz), 2.35 (2H, td, J = 7.5, 3.2 Hz),

2.62 (2H, dddd, J = 13.7, 9.3, 7.1, 5.6 Hz), 2.84 (2H, dddd, J = 13.4,

9.6, 9.3, 5.4 Hz), 4.04 (2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 13.9, 17.3, 22.5, 27.2, 29.6, 30.1, 31.7, 32.6, 32.8, 32.9,

37.6, 50.3, 56.0, 132.3, 173.2, 207.8, 208.6; HR-ESI-MS m/z: calcd for

compound 75, yellow oily liquid, yield 61.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.41–1.50 (2H, 1.43 (dddd, J = 13.2, 9.3, 7.1, 5.6 Hz), 1.48

(dddd, J = 14.1, 9.6, 9.3, 5.4 Hz)), 1.99 (1H, ddd, J = 17.9, 6.1, 1.4 Hz),

2.10 (2H, dddd, J = 13.2, 7.3, 5.4, 1.4 Hz), 2.19 (2H, dddd, J = 14.1,

5.6, 5.1, 1.4 Hz), 2.41 (3H, s), 2.66 (1H, ddd, J = 17.9, 8.5, 6.0 Hz), 4.04

(2H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.0, 20.5,

29.4, 37.7, 51.2, 60.2, 122.4, 171.0, 206.6, 207.6, 209.3; HR-ESI-MS m/

z: calcd for C₁₂H₁₄O₃{[M + H]⁺} 236.2670, found 236.0953; Anal. calcd

for C₁₂H₁₄O₃: C, 69.89; H, 6.84; O, 23.27; found: C, 69.84; H, 6.86; O,

23.29%.

C

₁₇H₂₆O₂{[M + H]⁺}262.3930, found 262.1840; Anal. calcd for

₁₇H₂₆O₂: C, 77.82; H, 9.99; O, 12.19; found: C, 77.80; H, 9.98; O,

12.22%.

compound 70, yellow oily liquid, yield 48.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.15–1.21 (4H, 1.16 (ddddd, J = 12.0, 7.0, 5.3, 1.7, 1.4

Hz), 1.21 (dddd, J = 11.7, 9.4, 7.6, 5.4 Hz)), 1.49–1.56 (4H, 1.51 (dddd,

J = 10.7, 6.8, 4.1, 1.7 Hz), 1.56 (dddd, J = 10.7, 8.1, 7.6, 7.0 Hz)), 1.92

(1H, dddd, J = 11.7, 7.0, 5.3, 1.4 Hz), 2.00 (1H, dddd, J = 13.4, 5.6, 5.1,

1.4 Hz), 2.12 (1H, ddd, J = 17.9, 6.1, 1.4 Hz), 2.19–2.31 (2H, 2.22

(dddd, J = 13.5, 9.3, 7.1, 5.6 Hz), 2.27 (dddd, J = 13.4, 9.6, 9.3, 5.4

Hz)), 2.45 (2H, ddd, J = 17.9, 8.5, 6.0 Hz), 2.71 (2H, ddd, J = 14.9, 8.5,

6.1 Hz), 4.05 (1H, dd, J = 9.6, 5.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ:

20.7, 24.9, 25.3, 27.6, 29.8, 30.8, 30.9, 38.5, 52.7, 125.9, 174.5, 211.6,

compound 76, yellow oily liquid, yield 42.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.15–1.31 (2H, 1.18 (dddd, J = 13.7, 7.3, 5.4, 1.4 Hz), 1.21

(dddd, J = 13.4, 9.6, 9.3, 5.4 Hz)), 2.12 (1H, dddd, J = 13.4, 5.6, 5.1,

1.4 Hz), 2.45 (2H, ddd, J = 14.9, 8.5, 6.1 Hz), 2.71 (2H, ddd, J = 17.9,

8.5, 6.0 Hz), 4.01–4.08 (3H, 4.03 (ddd, J = 17.9, 6.1, 1.4 Hz), 4.08 (dd,

J = 9.6, 5.1 Hz)); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.4, 28.1, 35.5,

37.8, 60.3, 65.2, 126.2, 169.1, 202.8, 207.1; HR-ESI-MS m/z: calcd for

14

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

C₁₀H₁₁ClO₂{[M + H]⁺} 198.6460, found 198.1207; Anal. calcd for

C, 74.11; H, 7.93; O, 17.95%.

C

₁₀H₁₁ClO₂: C, 60.46; H, 5.58; Cl, 17.85; O, 16.11; found: C, 60.40; H,

compound 143, yellow oily liquid, yield 82.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.89 (3H, t, J = 6.9 Hz), 1.05–1.43 (5H, 1.06 (qd, J = 6.9,

4.7 Hz), 1.27 (qd, J = 6.9, 4.7 Hz), 1.42 (dddd, J = 13.6, 5.6, 1.9, 1.4

Hz)), 1.56–1.67 (2H, 1.57 (dddd, J = 13.6, 10.0, 8.9, 5.7 Hz), 1.63

(dddtd, J = 10.0, 8.6, 5.8, 4.7, 1.9 Hz)), 2.01 (1H, ddd, J = 13.0, 8.6, 6.3

Hz), 2.16–2.24 (2H, 2.18 (ddd, J = 13.5, 8.9, 5.6 Hz), 2.23 (ddd, J =

13.5, 5.7, 1.4 Hz)), 4.04 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 12.0, 27.0, 29.5, 34.7, 35.9, 40.7, 47.8, 57.0, 126.2, 71.7,

200.7, 211.4; HR-ESI-MS m/z: calcd for C₁₂H₁₆O₂{[M + H]⁺}192.2580,

found 192.0031.0034; Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39; O,

16.64; found: C, 74.93; H, 8.39; O, 16.66%.

5.59; Cl, 17.86; O, 16.14%.

compound 77, yellow oily liquid, yield 55.7%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 6.5 Hz), 1.15–1.46 (10H, 1.17 (tt, J = 6.8,

6.5 Hz), 1.20 (h, J = 6.5 Hz), 1.25 (h, J = 6.5 Hz), 1.29 (tt, J = 6.8, 6.5

Hz), 1.44 (td, J = 6.8, 3.9 Hz)), 1.83 (1H, ddd, J = 17.9, 6.1, 1.4 Hz),

1.99 (1H, td, J = 3.9, 1.9 Hz), 2.08 (1H, td, J = 6.8, 3.9 Hz), 2.14–2.25

(2H, 2.14 (ddd, J = 16.9, 5.1, 1.4 Hz), 2.23 (ddd, J = 16.9, 9.6, 5.4 Hz)),

2.35 (2H, tddd, J = 6.4, 5.4, 1.9, 1.4 Hz), 2.54 (2H, d, J = 6.4 Hz),

4.05–4.12 (5H, 4.05 (dd, J = 9.6, 5.1 Hz), 4.12 (s)); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 14.4, 22.5, 27.7, 28.3, 31.9, 32.1, 37.7, 38.1, 39.1, 509,

52.3, 53.8, 55.2, 130.6, 170.8, 174.0, 205.3, 207.1; HR-ESI-MS m/z:

calcd for C₁₈H₂₆O₄{[M + H]⁺}306.4020, found 306.1296; Anal. calcd

for C₁₈H₂₆O₄: C, 70.56; H, 8.55; O, 20.89; found: C, 70.50; H, 8.56; O,

20.92%.

compound 144, yellow oily liquid, yield 81.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.84 (3H, t, J = 6.5 Hz), 1.04–1.41 (5H, 1.10 (td, J = 6.5,

4.1 Hz), 1.27 (h, J = 6.5 Hz), 1.41 (h, J = 6.5 Hz), 1.64–1.85 (4H, 1.65

(dddd, J = 13.7, 5.6, 1.9, 1.4 Hz), 1.81 (dddtd, J = 10.0, 8.6, 5.8, 4.1,

1.9 Hz)), 1.99 (1H, dd, J = 8.1, 6.3 Hz), 2.49 (2H, ddd, J = 13.4, 8.6, 6.3

Hz), 4.05 (2H, d, J = 16.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.7,

20.2, 27.4, 31.6, 35.9, 36.7, 39.3, 48.0, 57.2, 126.0, 169.6, 199.5, 210.3;

HR-ESI-MS m/z: calcd for C₁₃H₁₈O₂{[M + H]⁺}206.2850, found

206.1618; Anal. calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found:

C, 75.65; H, 8.82; O, 15.54%.

compound 78, yellow oily liquid, yield 47.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.19 (3H, d, J = 6.6 Hz), 1.89 (1H, ddd, J = 17.9, 6.1, 1.4

Hz), 2.00 (1H, ddd, J = 16.1, 8.5, 6.1 Hz), 2.33 (2H, ddd, J = 17.9, 8.5,

6.0 Hz), 2.35 (2H, ddd, J = 16.1, 6.0, 1.4 Hz), 4.05 (2H, dd, J = 8.7, 6.1

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.7, 26.9, 32.3, 38.0, 42.2, 45.1,

144.1, 150.1, 202.5, 204.4, 208.5; HR-ESI-MS m/z: calcd for

C₁₁H₁₂O₃{[M + H]⁺}192.2140, found 192.0076; Anal. calcd for

compound 145, yellow oily liquid, yield 80.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.82–0.89 (6H, 0.82 (t, J = 6.5 Hz), 0.89 (d, J = 6.9 Hz),

1.16–1.21 (4H, 1.16 (dq, J = 6.9, 6.5 Hz), 1.21 (dq, J = 6.9, 6.5 Hz)),

1.40 (1H, dd, J = 10.0, 5.8 Hz), 1.49–1.59 (2H, 1.51 (dddd, J = 13.8,

5.6, 4.1, 1.9 Hz), 1.54 (ddddd, J = 13.5, 5.8, 4.1, 1.8, 1.4 Hz)), 2.00 (1H,

dddd, J = 13.8, 10.0, 8.9, 1.8 Hz), 2.26–2.33 (3H, 2.28 (dddd, J = 13.4,

8.6, 6.3, 5.8 Hz), 2.30 (dddd, J = 13.4, 8.1, 5.8, 1.4 Hz), 2.32 (hd, J =

6.9, 2.5 Hz)), 4.03 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 11.9, 15.5, 24.7, 25.7, 29.3, 32.5, 42.0, 47.9, 54.5, 55.5,

124.9, 171.4, 204.5, 210.7; HR-ESI-MS m/z: calcd for C₁₄H₂₀O₂{[M +

H]⁺}220.3120, found 220.0761; Anal. calcd for C₁₄H₂₀O₂: C, 76.33; H,

9.15; O, 14.52; found: C, 76.29; H, 9.16; O, 14.55%.

C

₁₁H₁₂O₃: C, 68.74; H, 6.29; O, 24.97; found: C, 68.70; H, 6.30; O,

24.99%.

compound 139, yellow oily liquid, yield 86.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.14–1.24 (2H, 1.16 (ddddd, J = 14.7, 5.8, 4.1, 1.8, 1.4

Hz), 1.21 (ddddd, J = 13.6, 5.6, 4.1, 1.9, 1.4 Hz)), 1.46–1.57 (2H, 1.56

(ddd, J = 13.5, 8.9, 5.6 Hz), 1.54 (ddd, J = 13.5, 5.7, 1.4 Hz)), 1.92 (2H,

dddd, J = 13.0, 8.1, 5.8, 1.4 Hz), 2.00 (1H, d, J = 15.9 Hz), 2.19–2.32

(2H, 2.22 (d, J = 15.9 Hz), 2.29 (dd, J = 8.1, 6.3 Hz)), 4.04 (2H, dd, J =

8.6, 5.8 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 24.3, 25.9, 27.7, 35.9,

49.1, 56.6, 126.2, 168.0, 200.9, 208; HR-ESI-MS m/z: calcd for

C

₁₀H₁₂O₂{[M + H]⁺}164.2040, found 164.0788; Anal. calcd for

₁₀H₁₂O₂: C, 73.15; H, 7.37; O, 19.49; found: C, 73.11; H, 7.38; O,

compound 146, yellow oily liquid, yield 80.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (9H, s), 1.18 (1H, dd, J = 10.0, 5.8 Hz), 1.59–1.68

(2H, 1.59 (ddd, J = 13.3, 8.6, 6.3 Hz), 1.64 (dddd, J = 14.2, 10.0, 8.9,

5.7 Hz)), 1.80 (2H, ddd, J = 13.3, 8.1, 5.8 Hz), 1.99 (1H, ddd, J = 13.5,

8.9, 5.6 Hz), 2.13–2.30 (2H, 2.20 (ddd, J = 13.5, 5.7, 1.4 Hz), 2.28

19.52%.

compound 140, yellow oily liquid, yield 80.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, d, J = 6.7 Hz), 1.10–1.35 (4H, 1.12 (dddd, J =

13.2, 5.6, 4.1, 1.9 Hz), 1.17 (ddddd, J = 13.0, 10.0, 8.6, 5.8, 1.9 Hz),

1.25 (dddd, J = 13.2, 10.0, 8.9, 1.8 Hz), 1.30 (dddd, J = 13.0, 8.1, 5.8,

1.4 Hz)), 1.43 (2H, dddd, J = 13.0, 8.6, 6.3, 5.8 Hz), 2.00 (1H, dqd, J =

8.9, 6.7, 5.6 Hz), 3.35 (1H, d, J = 15.9 Hz), 4.05 (2H, dd, J = 8.1, 6.3

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 21.0, 27.9, 34.0, 36.2, 41.6, 52.8,

56.6, 126.0, 170.4, 204.2, 209.0; HR-ESI-MS m/z: calcd for

(dddd, J = 14.2, 5.6, 1.9, 1.4 Hz)), 4.05 (2H, dd, J = 8.1, 6.3 Hz); ¹³

C

NMR (100 MHz, DMSO‑d₆) δ: 27.5, 27.6, 31.5, 32.5, 36.1, 46.2, 47.9,

55.5, 125.6, 169.2, 201.8, 210.7; HR-ESI-MS m/z: calcd for

C

₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1653; Anal. calcd for

C₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.29; H, 9.17; O,

14.56%.

C

₁₁H₁₄O₂{[M + H]⁺}178.2310, found 178.1312; Anal. calcd for

C₁₁H₁₄O₂: C, 74.13; H, 7.92; O, 17.95; found: C, 74.10; H, 7.91; O,

17.97%.

compound 147, yellow oily liquid, yield 78.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (3H, t, J = 6.5 Hz), 1.10–1.45 (9H, 1.17 (tt, J = 6.8,

6.5 Hz), 1.24 (td, J = 6.8, 4.3 Hz), 1.32 (td, J = 6.8, 4.3 Hz), 1.36 (tq, J

= 6.9, 6.5 Hz), 1.42 (ddd, J = 13.4, 8.6, 6.3 Hz)), 1.66 (2H, tt, J = 6.9,

6.5 Hz), 2.00 (1H, dd, J = 8.9, 5.7 Hz), 2.17 (2H, dddd, J = 10.0, 8.6,

5.8, 4.3, 1.9 Hz), 2.38 (2H, dddd, J = 13.7, 5.6, 1.9, 1.4 Hz), 4.05 (2H,

dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.1, 22.7, 25.3,

27.0, 31.6, 32.3, 34.0, 35.8, 40.6, 48.1, 57.3, 125.7, 168.8, 201.8, 210.0;

HR-ESI-MS m/z: calcd for C₁₅H₂₂O₂{[M + H]⁺}234.3390, found

234.1933; Anal. calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found:

C, 76.83; H, 9.47; O, 13.66%.

compound 141, yellow oily liquid, yield 81.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (3H, d, J = 7.0 Hz), 1.17–1.36 (2H, 1.22 (dddd, J =

14.6, 8.6, 5.8, 1.9 Hz), 1.32 (dddd, J = 13.3, 8.1, 5.8, 1.4 Hz)), 1.41 (1H,

dddd, J = 14.6, 5.8, 4.1, 1.4 Hz), 2.00 (1H, dddd, J = 13.3, 8.6, 6.3, 5.8

Hz), 2.19 (2H, dd, J = 13.8, 5.6 Hz), 2.38 (2H, dd, J = 13.8, 1.4 Hz),

4.05 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.3,

31.5, 34.6, 35.6, 45.2, 49.8, 56.6, 125.9, 170.1, 200.7, 208.0; HR-ESI-

MS m/z: calcd for C₁₁H₁₄O₂{[M + H]⁺}178.2310, found 178.1308;

Anal. calcd for C₁₁H₁₄O₂: C, 74.13; H, 7.92; O, 17.95; found: C, 74.10; H,

7.92; O, 17.96%.

compound 148, yellow oily liquid, yield 77.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.73–0.80 (9H, 0.75 (t, J = 7.1 Hz), 0.80 (q, J = 7.1 Hz)),

1.00 (1H, ddd, J = 10.0, 8.6, 5.8, 1.9 Hz), 1.16–1.24 (2H, 1.18 (ddd, J =

13.3, 8.1, 5.8 Hz), 1.21 (dddd, J = 14.2, 10.0, 8.9, 5.7 Hz)), 1.91 (2H,

dddd, J = 14.2, 5.6, 1.9, 1.4 Hz), 2.02 (1H, ddd, J = 13.3, 8.6, 6.3 Hz),

compound 142, yellow oily liquid, yield 82.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (3H, d, J = 6.9 Hz), 1.08–1.22 (2H, 1.10 (ddd, J =

13.0, 8.6, 6.3 Hz), 1.185 (dddd, J = 13.3, 10.0, 8.9, 5.7 Hz)), 1.48 (1H,

dddd, J = 13.3, 5.6, 1.9, 1.4 Hz), 1.63–1.76 (4H, 1.66 (dddd, J = 10.0,

8.6, 6.9, 5.8, 1.9 Hz), 1.71 (ddd, J = 13.0, 8.1, 5.8 Hz)), 2.00 (1H, d, J =

16.1 Hz), 4.05 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 22.5, 29.4, 32.1, 36.0, 40.2, 47.9, 55.0, 126.3, 168.9, 201.3, 208.5;

HR-ESI-MS m/z: calcd for C₁₁H₁₄O₂{[M + H]⁺}178.2310, found

178.1313; Anal. calcd for C₁₁H₁₄O₂: C, 74.13; H, 7.92; O, 17.95; found:

2.25 (2H, ddd, J = 13.5, 8.9, 5.6 Hz), 4.02 (2H, dd, J = 8.1, 6.3 Hz); ¹³

C

NMR (100 MHz, DMSO‑d₆) δ: 8.4, 24.5, 27.1, 32.9, 34.6, 34.8, 35.4,

43.6, 49.1, 60.1, 126.4, 170.5, 200.1, 210.8; HR-ESI-MS m/z: calcd for

C

₁₅H₂₂O₂{[M + H]⁺}234.3390, found 234.1083; Anal. calcd for

₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found: C, 76.84; H, 9.48; O,

15

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

13.65%.

(2H, ddd, J = 13.4, 8.6, 6.3 Hz), 2.71 (2H, ddd, J = 13.5, 8.9, 5.6 Hz),

4.05 (2H, dd, J = 8.1, 6.3 Hz), 6.70 (2H, ddd, J = 8.2, 2.6, 0.5 Hz), 7.07

(2H, ddd, J = 8.2, 1.0, 0.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 33.8,

34.8, 37.0, 39.6, 48.7, 60.1, 121.7, 127.6, 132.3, 134.7, 161.1, 162.2,

198.2, 206.2; HR-ESI-MS m/z: calcd for C₁₆H₁₆O₃{[M + H]⁺}256.3010,

found 256.1772; Anal. calcd for C₁₆H₁₆O₃: C, 74.98; H, 6.29; O, 18.73;

found: C, 74.94; H, 6.31; O, 18.76%.

compound 149, yellow oily liquid, yield 81.0%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.09 (2H, ddd, J = 14.2, 4.7, 3.9, 1.9 Hz), 1.24 (2H, dddd,

J = 14.1, 10.0, 8.9, 1.8 Hz), 1.57–1.70 (4H, 1.60 (dddd, J = 13.4, 8.6,

6.3, 5.8 Hz), 1.68 (dddd, J = 13.4, 8.1, 5.8, 1.4 Hz)), 1.75–1.89 (2H,

1.77 (ddddd, J = 13.5, 10.0, 8.6, 5.8, 1.9 Hz), 1.86 (dddd, J = 14.1, 5.6,

4.1, 1.9 Hz)), 2.00 (1H, dd, J = 13.5, 5.8, Hz), 2.14–2.26 (2H, 2.14

(ddd, J = 14.3, 10.0, 4.0 Hz), 2.24 (ddd, J = 14.3, 3.9, 1.9 Hz)), 2.48

(1H, dd, J = 13.5, 3.9 Hz), 2.63–2.76 (2H, 2.65 (ddddd, J = 13.5, 4.0,

3.5, 2.1, 1.9 Hz), 2.74 (dddd, J = 14.2, 10.0, 4.7, 4.0 Hz)), 4.05 (2H, dd,

J = 8.1, 6.3 Hz)), 5.62 (1H, t, J = 4.7 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 16.2, 22.6, 23.0, 25.3, 27.2, 27.6, 31.9, 42.1, 49.2, 58.2, 123.0, 128.8,

136.6, 174.9, 198.9, 210.5; HR-ESI-MS m/z: calcd for C₁₆H₂₀O₂{[M +

H]⁺}244.3340, found 244.2134; Anal. calcd for C₁₆H₂₀O₂: C, 78.65; H,

8.25; O, 13.10; found: C, 78.61; H, 8.27; O, 13.12%.

compound 155, yellow oily liquid, yield 66.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.08–1.30 (2H, 1.12 (ddddd, J = 14.8, 10.0, 8.6, 5.8, 1.9

Hz), 1.23 (ddddd, J = 14.8, 5.8, 4.1, 1.8, 1.4 Hz)), 1.47 (2H, dddd, J =

13.2, 8.1, 5.8, 1.4 Hz), 1.63–1.76 (2H, 1.66 (dddd, J = 13.1, 10.0, 8.9,

1.8 Hz), 1.72 (dddd, J = 13.2, 8.6, 6.3, 5.8 Hz)), 2.00 (1H, dddd, J =

13.1, 5.6, 4.1, 1.9 Hz), 2.19 (3H, s), 3.39 (1H, d, J = 16.2 Hz), 4.03 (2H,

dd, J = 8.9, 5.6 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 16.1, 24.3, 25.9,

29.3, 48.5, 52.8, 59.7, 126.0, 168.7, 199.5, 204.8, 208.3; HR-ESI-MS m/

z: calcd for C₁₂H₁₄O₃{[M + H]⁺}206.2410, found 206.0268; Anal. calcd

for C₁₂H₁₄O₃: 69.89; H, 6.84; O, 23.27; found: 69.85; H, 6.86; O,

23.28%.

compound 150, yellow oily liquid, yield 80.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.85–1.95 (2H, 1.87 (dddd, J = 14.1, 5.6, 4.1, 1.9 Hz), 1.94

(ddddd, J = 13.5, 5.8, 4.1, 1.8, 1.4 Hz)), 2.05 (1H, dddd, J = 14.1, 10.0,

8.9, 1.8 Hz), 2.25 (2H, dddd, J = 13.4, 8.6, 6.3, 5.8 Hz), 2.54–2.65 (2H,

2.54 (dddd, J = 13.4, 8.1, 5.8, 1.4 Hz), 2.63 (ddddd, J = 13.5, 10.0, 8.6,

5.8, 1.9 Hz)), 3.07 (1H, d, J = 15.9 Hz), 3.74 (2H, dd, J = 8.9, 5.6 Hz),

7.21–7.36 (5H, 7.23 (tt, J = 7.7, 1.3 Hz), 7.232 (4H, 7.31 (dddd, J = 7.8,

7.7, 1.9, 0.5 Hz), 7.35 (dddd, J = 7.8, 1.3, 1.2, 0.5 Hz)); ¹³C NMR (100

MHz, DMSO‑d₆) δ: 21.6, 26.9, 41.3, 50.8, 56.6, 64.2, 126.4, 126.7,

127.2, 128.8, 145.8, 170.3, 204.4, 210.5; HR-ESI-MS m/z: calcd for

C₁₆H₁₆O₂{[M + H]⁺}240.3020, found 240.1956; Anal. calcd for

compound 156, yellow oily liquid, yield 67.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (3H, t, J = 7.1 Hz), 1.48–1.81 (4H, 1.53 (ddddd, J =

13.7, 10.0, 8.6, 5.8, 1.9 Hz), 1.64 (ddddd, J = 13.7, 5.8, 4.1, 1.8, 1.4 Hz),

1.77 (dddd, J = 13.1, 10.0, 8.9, 1.8 Hz)), 2.00 (1H, dddd, J = 13.1, 5.6,

4.1, 1.9 Hz), 2.26 (2H, dddd, J = 13.2, 8.6, 6.3, 5.8 Hz), 3.36 (1H, d, J =

16.2 Hz), 4.00–4.09 (4H, 3.55 (dd, J = 8.1, 6.3 Hz), 4.09 (q, J = 7.1

Hz)); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.0, 14.2, 26.9, 33.7, 41.7,

56.9, 59.9, 64.0, 123.9, 172.9, 174.7, 198.5, 206.0; HR-ESI-MS m/z:

calcd for C₁₃H₁₆O₄{[M + H]⁺}236.2670, found 236.1727; Anal. calcd

for C₁₃H₁₆O₄: C, 66.09; H, 6.83; O, 27.09; found: C, 66.05; H, 6.84; O,

27.81%.

C

₁₆H₁₆O₂: C, 79.97; H, 6.71; O, 13.32; found: C, 79.94; H, 6.73; O,

13.34%.

compound 151, yellow oily liquid, yield 76.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 6.5 Hz), 0.98 (1H, dd, J = 10.3, 5.8 Hz),

1.10–1.32 (13H, 1.10 (dddd, J = 13.9, 5.6, 1.9, 1.4 Hz), 1.16 (dq, J =

12.9, 2.8 Hz), 1.64–1.74 (4H, 1.64 (dddd, J = 13.9, 10.0, 8.9, 5.7 Hz),

1.69 (ddd, J = 13.5, 8.9, 5.6 Hz)), 1.92 (1H, ddd, J = 13.2, 8.1, 5.8 Hz),

2.00 (1H, ddd, J = 13.2, 8.6, 6.3 Hz), 2.51 (2H, ddd, J = 13.5, 5.7, 1.4

Hz), 4.04 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ:

14.5, 20.2, 27.4, 30.0, 30.4, 33.6, 33.8, 35.2, 37.7, 37.8, 42.4, 50.2,

64.1, 125.3, 169.6, 200.0, 208.8; HR-ESI-MS m/z: calcd for

compound 157, yellow oily liquid, yield 53.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.14–1.23 (2H, 1.15 (ddddd, J = 13.2, 5.8, 4.1, 1.8, 1.4

Hz), 1.20 (ddddd, J = 13.2, 10.0, 8.6, 5.8, 1.9 Hz)), 1.41 (2H, dddd, J =

15.2, 10.0, 8.9, 1.8 Hz), 1.91 (2H, dddd, J = 15.2, 5.6, 4.1, 1.9 Hz), 1.98

(1H, dddd, J = 13.2, 8.1, 5.8, 1.4 Hz), 2.50 (2H, dddd, J = 13.2, 8.6, 6.3,

5.8 Hz), 3.87 (1H, dd, J = 8.9, 5.6 Hz), 4.04 (2H, dd, J = 8.1, 6.3 Hz); ¹³

C

NMR (100 MHz, DMSO‑d₆) δ: 120.4, 24.1, 26.1, 30.2, 43.6, 57.0, 60.1,

125.8, 170.9, 173.3, 204.0, 207.3; HR-ESI-MS m/z: calcd for

C₁₂H₁₅NO₃{[M + H]⁺}221.2560, found 221.1534; Anal. calcd for

C

₁₉H₂₈O₂{[M + H]⁺}288.4310, found 288.1799; Anal. calcd for

₁₉H₂₈O₂: C, 79.12; H, 9.79; O, 11.09; found: C, 79.10; H, 9.78; O,

C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33; O, 21.69; found: C, 65.10; H,

11.10%.

6.85; N, 6.34; O, 21.68%.

compound 152, yellow oily liquid, yield 73.3%; ¹H NMR (400 MHz,

compound 158, yellow oily liquid, yield 56.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (9H, s), 1.42 (2H, dddd, J = 11.4, 10.0, 8.9, 5.7 Hz),

1.92 (2H, ddd, J = 13.4, 8.1, 5.8 Hz), 2.00 (1H, dddd, J = 11.4, 5.6, 1.9,

1.4 Hz), 2.10 (2H, ddd, J = 13.1, 8.9, 5.6 Hz), 3.85 (1H, d, J = 16.1 Hz),

4.03 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 27.9,

28.9, 29.4, 31.6, 47.5, 60.2, 60.3, 77.2, 124.4, 156.2, 170.6, 201.3,

207.6; HR-ESI-MS m/z: calcd for C₁₅H₂₁NO₄{[M + H]⁺}279.3360,

found 279.0583; Anal. calcd for C₁₅H₂₁NO₄: C, 64.50; H, 7.58; N, 5.01;

O, 22.91; found: C, 64.48; H, 7.59; N, 5.01; O, 22.92%.

DMSO‑d₆) δ: 1.06–1.22 (2H, 1.07 (dddd, J = 13.9, 10.0, 8.9, 5.7 Hz),

1.17 (dt, J = 14.2, 2.8 Hz)), 1.35–1.46 (8H, 1.38 (qt, J = 10.3, 2.8 Hz),

1.46 (dtd, J = 13.0, 10.3, 2.8 Hz)), 1.69 (2H, dt, J = 14.1, 2.8 Hz), 2.00

(1H, ddd, J = 14.2, 10.3, 2.8 Hz), 2.18–2.38 (4H, 2.21 (ddd, J = 13.5,

8.9, 5.6 Hz), 2.35 (ddd, J = 13.5, 5.7, 1.4 Hz)), 3.83 (4H, 3.85 (ddd, J =

14.6, 5.6, 1.4 Hz), 4.05 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 20.2, 30.4, 33.6, 33.8, 35.2, 37.7, 42.4, 52.0, 58.2, 64.1,

119.1, 127.0, 168.7, 196.8, 208.7; HR-ESI-MS m/z: calcd for

C₁₈H₂₄O₄{[M + H]⁺}304.3860, found 304.1028; Anal. calcd for

compound 159, yellow oily liquid, yield 61.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.16 (2H, ddddd, J = 14.7, 10.0, 8.6, 5.8, 1.9 Hz), 1.41 (2H,

ddddd, J = 14.7, 5.8, 4.1, 1.8, 1.4 Hz), 1.91 (2H, dddd, J = 12.7, 8.1,

5.8, 1.4 Hz), 1.99 (1H, dddd, J = 14.1, 10.0, 8.9, 1.8 Hz), 3.88 (1H, dd, J

= 8.9, 5.6 Hz), 4.03 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 19.1, 25.8, 37.7, 43.7, 57.4, 64.3, 126.4, 170.5, 202.9,

209.2; HR-ESI-MS m/z: calcd for C₁₀H₁₁ClO₂{[M + H]⁺}198.6460,

found 198.0818; Anal. calcd for C₁₀H₁₁ClO₂: C, 60.46; H, 5.58; Cl,

17.85; O, 16.11; found: C, 60.43; H, 5.59; Cl, 17.86; O, 16.10%.

compound 160, yellow oily liquid, yield 61.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86–1.00 (6H, 0.86 (s), 0.99 (s)), 1.16–1.27 (2H, 1.19

(ddd, J = 15.0, 8.6, 5.8 Hz), 1.22 (ddd, J = 15.0, 5.8, 1.4 Hz)), 1.47–1.56

(1.50 (dddd, J = 13.4, 8.1, 5.8, 1.4 Hz), 1.52 (ddd, J = 13.4, 8.6, 6.3, 5.8

Hz), 1.93 (2H, d, J = 15.4 Hz), 2.00 (1H, d, J = 15.4 Hz), 4.05 (2H, dd, J

= 8.1, 6.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 22.5, 28.7, 32.1, 42.5,

46.9, 51.1, 54.8, 124.1, 168.9, 197.6, 209.9; HR-ESI-MS m/z: calcd for

C

₁₈H₂₄O₄: C, 71.03; H, 7.95; O, 21.02; found: C, 71.00; H, 7.96; O,

21.04%.

compound 153, yellow oily liquid, yield 70.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.16 (2H, dddd, J = 13.8, 10.0, 8.9, 5.7 Hz), 1.91 (2H,

dddd, J = 13.8, 5.6, 1.9, 1.4 Hz), 1.99 (1H, ddd, J = 13.1, 8.6, 6.3 Hz),

2.50 (2H, ddd, J = 13.1, 8.1, 5.8 Hz), 3.45 (1H, ddd, J = 13.5, 8.9, 5.6

Hz), 4.04 (2 h, dd, J = 8.1, 6.3 Hz), 7.57–7.70 (4H, 7.60 (ddd, J = 7.8,

1.3, 0.5 Hz), 7.67 (ddd, J = 7.8, 7.6, 1.3 Hz)); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 24.9, 32.3, 32.8, 48.1, 57.0, 68.3, 123.0, 128.3, 134.5,

140.0, 168.7, 199.0, 200.1, 209.8; HR-ESI-MS m/z: calcd for C₁₈H₁₅NO₄

{[M + H]⁺}309.4001, found 309.2209; Anal. calcd for C₁₈H₁₅NO₄: C,

69.89; H, 4.89; N, 4.53; O, 20.69; found: C, 69.84; H, 4.88; N, 4.56; O,

20.71%.

compound 154, yellow oily liquid, yield 71.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (2H, dddd, J = 14.2, 5.6, 1.9, 1.4 Hz), 1.93 (1H, dddd,

J = 14.2, 10.0, 8.9, 5.7 Hz), 2.01 (1H, ddd, J = 13.4, 8.1, 5.8 Hz), 2.11

C

₁₂H₁₆O₂{[M + H]⁺}192.2580, found 192.1460; Anal. calcd for

16

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

C₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found: C, 74.93; H, 8.40; O,

16.65%.

(dddd, J = 14.1, 3.3, 2.5, 2.3 Hz)), 2.00 (1H, qt, J = 10.3, 2.8 Hz), 4.03

(2H, dd, J = 10.3, 3.0 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.5, 23.0,

24.2, 28.4, 29.3, 30.2, 33.1, 33.7, 36.2, 37.2, 37.9, 42.6, 49.5, 59.4,

128.8, 169.4, 199.8, 207.6; HR-ESI-MS m/z: calcd for C₂₀H₃₀O₂{[M +

H]⁺}302.4580, found 302.1896; Anal. calcd for C₂₀H₃₀O₂: C, 79.42; H,

10.00; O, 10.58; found: C, 79.40; H, 10.01; O, 10.59%.

compound 161, yellow oily liquid, yield 58.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.80–0.89 (6H, 0.0.83 (d, J = 6.9 Hz), 0.87 (s)), 0.98 (3H,

s), 1.17–1.28 (2H, 1.24 (dd, J = 15.0, 5.8 Hz), 1.27 (dd, J = 15.0, 1.4

Hz)), 1.56 (1H, ddd, J = 8.1, 6.9, 5.8, 1.4 Hz), 1.93 (2H, d, J = 15.6 Hz),

2.00 (1H, d, J = 15.6 Hz), 4.05 (2H, d, J = 8.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 23.0, 26.2, 27.3, 33.7, 45.2, 48.0, 66.1, 125.9, 162.7,

198.9, 207.2; HR-ESI-MS m/z: calcd for C₁₃H₁₈O₂{[M + H]⁺}206.2850,

found 206.1255; Anal. calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51;

found: C, 75.65; H, 8.82; O, 15.53%.

compound 168, yellow oily liquid, yield 55.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.20 (2H, dtd, J = 14.1, 10.2, 3.4 Hz), 2.01 (1H, dddd, J =

14.1, 3.3, 2.5, 2.3 Hz), 2.25 (2H, ddd, J = 14.1, 3.0, 2.6 Hz), 2.50 (2H,

dt, J = 14.1, 10.3 Hz), 3.53 (1H, dd, J = 10.3, 3.0 Hz), 4.07 (2H, tdd, J =

10.2, 2.6, 2.5 Hz), 5.25 (2H, s), 7.26 (1H, tt, J = 7.7, 1.3 Hz), 7.33–7.40

(4H, 7.36 (dddd, J = 7.8, 1.3, 1.0, 0.6 Hz), 7.40 (dddd, J = 7.8, 7.7, 1.6,

0.6 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 28.2, 29.1, 31.7, 45.3, 56.7,

60.3, 63.6, 126.9, 127.1, 128.5, 128.9, 136.1, 156.2, 170.8, 198.3,

208.5; HR-ESI-MS m/z: calcd for C₁₈H₁₉NO₄{[M + H]⁺}313.3530,

found 313.1009; Anal. calcd for C₁₈H₁₉NO₄: C, 69.00; H, 6.11; N, 4.47;

O, 20.42; found: C, 68.96; H, 6.12; N, 4.49; O, 20.41%.

compound 162, yellow oily liquid, yield 53.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (3H, d, J = 6.9 Hz), 1.19–1.65 (7H, 1.22 (3H, s), 1.36

(dddd, J = 13.2, 10.0, 8.9, 1.8 Hz), 1.59 (ddddd, J = 13.4, 5.8, 4.1, 1.8,

1.4 Hz), 1.85 (2H, ddd, J = 13.3, 5.8, 1.4 Hz), 2.00 (1H, ddd, J = 13.3,

8.6, 5.8 Hz), 4.04 (2H, d, J = 16.1 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ:

19.2, 20.2, 27.7, 30.8, 33.5, 34.6, 42.4, 44.9, 126.0, 170.1, 212.7, 215.0;

HR-ESI-MS m/z: calcd for C₁₂H₁₆O₂{[M + H]⁺}192.2580, found

192.1462; Anal. calcd for C₁₃H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found:

C, 74.93; H, 8.41; O, 16.67%.

compound 169 , yellow oily liquid, yield 89.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.14–1.24 (2H, 1.16 (ddddd, J = 13.8, 3.1, 2.9, 2.8, 2.4

Hz), 1.18 (dtdd, J = 13.8, 10.2, 3.4, 2.8 Hz)), 1.54 (2H, dtt, J = 13.5,

10.3, 2.8 Hz), 1.92 (2H, dtd, J = 13.5, 2.8, 2.5 Hz), 2.00 (1H, dtd, J =

13.5, 10.2, 2.7 Hz), 2.19–2.32 (4H, 2.22 (ddd, J = 13.9, 3.4, 2.4 Hz),

compound 163, yellow oily liquid, yield 50.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.15 (3H, d, J = 6.9 Hz), 1.41 (3H, s), 1.91 (2H, dddd, J =

13.7, 5.6, 4.1, 1.9 Hz), 2.00 (1H, dddd, J = 13.7, 10.0, 8.9, 1.8 Hz), 2.10

(2H, dddd, J = 13.3, 4.1, 1.8, 1.4 Hz), 2.33 (1H, ddd, J = 13.3, 5.8, 1.9

Hz), 2.58 (2H, ddd, J = 8.1, 5.8, 1.4 Hz), 4.05 (2H, ddd, J = 8.9, 6.9, 5.6

Hz), 4.66 (2H, d, J = 1.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.7,

21.8, 29.4, 34.7, 36.5, 45.4, 60.2, 64.0, 115.5, 127.0, 153.1, 172.6,

197.7, 207.0; HR-ESI-MS m/z: calcd for C₁₄H₁₈O₂{[M + H]⁺}218.2960,

found 218.1618; Anal. calcd for C₁₄H₁₈O₂: C, 77.03; H, 8.31; O, 14.66;

found: C, 77.00; H, 8.32; O, 14.68%.

2.29 (ddd, J = 13.9, 10.2, 3.1 Hz)), 4.07 (2H, dd, J = 10.2, 2.5 Hz); ¹³

C

NMR (100 MHz, DMSO‑d₆) δ: 25.4, 26.0, 29.1, 32.9, 36.2, 41.6, 52.8,

125.9, 170.3, 201.9, 211.8; HR-ESI-MS m/z: calcd for C₁₁H₁₄O₂{[M +

H]⁺}178.2310, found 178.0826; Anal. calcd for C₁₁H₁₄O₂: C, 74.13; H,

7.92; O, 17.95; found: C, 74.10; H, 7.93; O, 17.96%.

compound 170, yellow oily liquid, yield 86.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.87 (3H, d, J = 6.7 Hz), 1.17 (2H, dtt, J = 13.3, 10.3, 2.8

Hz), 1.48–1.58 (2H, 1.51 (ddtd, J = 13.3, 2.9, 2.8, 2.7 Hz), 1.56 (dddd, J

= 14.1, 2.9, 2.8, 2.4 Hz)), 1.66–1.82 (2H, 1.68 (dddd, J = 14.1, 10.3,

3.4, 2.8 Hz), 1.76 (dtd, J = 13.5, 2.8, 2.5 Hz)), 2.00 (1H, dtd, J = 13.5,

10.2, 2.7 Hz), 2.10 (1H, ddd, J = 16.2, 6.1, 1.4 Hz), 2.27 (2H, dd, J =

6.7, 32.4 Hz), 4.04 (2H, dd, J = 10.2, 2.5 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 19.1, 25.4, 26.0, 32.9, 33.9, 36.2, 40.2, 52.8, 125.8, 172.3,

204.8, 211.8; HR-ESI-MS m/z: calcd for C₁₂H₁₆O₂{[M + H]⁺}192.2580,

found 192.1100; Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64;

found: C, 74.93; H, 8.41; O, 16.66%.

compound 164, yellow oily liquid, yield 51.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.78–0.99 (9H, 0.80 (d, J = 6.9 Hz), 0.89 (d, J = 6.9 Hz)),

1.31–1.36 (4H, 1.32 (dddd, J = 14.2, 5.6, 4.1, 1.9 Hz), 1.36 (dddd, J =

13.8, 4.1, 1.8, 1.4 Hz)), 1.82 (1H, dddd, J = 14.2, 10.0, 8.9, 1.8 Hz), 2.00

(1H, dddd, J = 13.8, 10.0, 5.8, 1.9 Hz), 2.09 (1H, dqdd, J = 8.1, 6.9, 5.8,

1.4 Hz), 2.17 (1H, dd, J = 6.9, 2.5 Hz), 4.05 (1H, d, J = 8.1 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 18.8, 21.1, 25.7, 26.6, 27.9, 33.9, 50.6, 55.2,

56.8, 126.2, 170.0, 203.2, 209.9; HR-ESI-MS m/z: calcd for

C₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1411; Anal. calcd for

compound 171, yellow oily liquid, yield 87.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, d, J = 7.0 Hz), 1.19 (1H, dtd, J = 12.8, 2.8, 2.7

Hz), 1.50–1.68 (2H, 1.55 (dtd, J = 12.8, 10.3, 2.9 Hz), 1.63 (dddd, J =

10.2, 7.0, 3.4, 2.8 Hz)), 1.80 (2H, dtd, J = 13.4, 2.8, 2.5 Hz), 1.99 (1H,

dtd, J = 13.4, 10.2, 2.7 Hz), 2.09 (2H, dd, J = 14.1, 10.2 Hz), 2.65 (2H,

ddd, J = 16.2, 8.5, 6.2 Hz)), 4.03 (2H, dd, J = 10.2, 2.5 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 24.4, 31.5, 33.4, 34.5, 35.8, 42.0, 45.2, 56.3,

125.9, 173.6, 207.3, 201.9; HR-ESI-MS m/z: calcd for C₁₂H₁₆O₂{[M +

H]⁺}192.2580, found 192.1098; Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H,

8.39; O, 16.64; found: C, 74.93; H, 8.40; O, 16.67%.

C

₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.30; H, 9.17; O,

14.51%.

compound 165, yellow oily liquid, yield 49.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.85 (2H, ddd, J = 14.6, 3.9, 1.9 Hz), 2.00 (1H, ddd, J =

13.4, 10.0, 3.9 Hz), 2.12 (2H, ddd, J = 13.4, 3.9, 1.9 Hz), 2.19 (2H, ddd,

J = 14.6, 10.0, 3.9 Hz), 2.48–2.55 (2H, 2.51 (d, J = 16.3 Hz), 2.54 (dd, J

= 14.6, 3.6 Hz)), 4.03 (2H, dd, J = 10.1, 3.6 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 29.1, 40.0, 41.1, 47.6, 56.6, 126.3, 161.4, 199.9, 204.1,

210.4; HR-ESI-MS m/z: calcd for C₁₀H₁₀O₃{[M + H]⁺}178.1870, found

178.0059; Anal. calcd for C₁₀H₁₀O₃: C, 67.41; H, 5.66; O, 26.94; found:

C, 67.38; H, 5.67; O, 26.96%.

compound 172, yellow oily liquid, yield 87.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, d, J = 7.0 Hz), 1.18 (1H, dddd, J = 14.1, 3.1, 2.9,

2.4 Hz), 1.58–1.78 (2H, 1.60 (dddd, J = 14.1, 10.2, 3.4, 2.8 Hz), 1.77

(qdtd, J = 7.0, 2.9, 2.8, 2.7 Hz)), 2.00 (1H, ddd, J = 14.2, 2.8, 2.5 Hz),

2.11 (2H, ddd, J = 14.2, 10.2, 2.7 Hz), 2.43 (2H, ddd, J = 13.8, 3.4, 2.4

Hz), 2.71 (2H, ddd, J = 13.8, 10.2, 3.1 Hz), 4.03 (2H, dd, J = 10.2, 2.5

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.3, 21.1, 29.3, 33.7, 34.8, 35.8,

40.6, 60.1, 125.8, 172.3, 206.2, 210.2; HR-ESI-MS m/z: calcd for

compound 166, yellow oily liquid, yield 38.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.15–1.21 (2H, 1.17 (dddd, J = 13.8, 10.0, 8.9, 5.7 Hz),

1.19 (ddd, J = 13.6, 8.1, 5.8 Hz)), 1.91 (2H, dddd, J = 13.8, 5.6, 1.9, 1.4

Hz), 2.01 (1H, ddd, J = 13.6, 8.6, 6.3 Hz), 2.23–2.30 (2H, 2.25 (ddd, J =

13.1, 8.9, 5.6 Hz), 2.29 (ddd, J = 13.1, 5.7, 1.4 Hz)), 2.58 (1H, dd, J =

8.6, 1.9 Hz), 4.04 (2H, dd, J = 8.1, 6.3 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 29.6, 30.0, 35.2, 46.7, 50.1, 60.2, 126.3, 169.2, 194.3,

208.2; HR-ESI-MS m/z: calcd for C₁₀H₁₃NO₂{[M + H]⁺}179.2190,

found 179.0762; Anal. calcd for C₁₀H₁₃NO₂: C, 67.02; H, 7.31; N, 7.82;

O, 17.85; found: C, 67.00; H, 7.33; N, 7.81; O, 17.87%.

C

₁₂H₁₆O₂{[M + H]⁺}192.2580, found 192.0995; Anal. calcd for

C₁₂H₁₆O₂: C, 74.97; H, 8.39; O, 16.64; found: C, 74.92; H, 8.41; O,

16.63%.

compound 173, yellow oily liquid, yield 85.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.88 (3H, t, J = 6.9 Hz), 1.12–1.31 (2H, 1.18 (qd, J = 6.9,

3.7 Hz), 1.24 (qd, J = 6.9, 3.7 Hz)), 1.65–1.84 (2H, 1.67 (dddd, J = 14.1,

3.1, 2.9, 2.4 Hz), 1.80 (dddd, J = 14.1, 10.2, 3.4, 2.8 Hz)), 1.92 (1H,

tdtd, J = 3.7, 2.9, 2.8, 2.7 Hz), 1.99 (1H, ddd, J = 13.5, 2.8, 2.5 Hz), 2.11

(2H, ddd, J = 13.5, 10.2, 2.7 Hz), 2.66 (2H, ddd, J = 13.7, 3.4, 2.4 Hz),

2.38 (2H, ddd, J = 13.7, 10.2, 3.1 Hz), 4.05 (2H, dd, J = 10.2, 2.5 Hz);

compound 167, yellow oily liquid, yield 71.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.5 Hz), 0.96–1.35 (11H, 0.98 (ddd, J =

14.1, 10.2, 3.4 Hz), 1.07 (ddd, J = 12.9, 10.3, 2.8 Hz), 1.19 (ddd, J =

12.9, 10.3, 2.8 Hz), 1.21 (dq, J = 12.9, 2.8 Hz), 1.26 (dq, J = 12.9, 2.8

Hz), 1.35 (qdd, J = 10.2, 2.6, 2.5 Hz)), 1.60–1.81 (8H, 1.64 (td, J = 6.8,

4.7 Hz), 1.69 (td, J = 6.8, 4.7 Hz), 1.72 (ttt, J = 10.3, 4.7, 2.8 Hz), 1.80

17

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

¹³C NMR (100 MHz, DMSO‑d₆) δ: 12.0, 27.0, 28.1, 32.6, 34.9, 35.9,

38.7, 40.6, 51.6, 125.1, 173.6, 207.8, 211.3; HR-ESI-MS m/z: calcd for

C₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.1617; Anal. calcd for

3.5, 2.2 Hz)), 1.78 (2H, ddddd, J = 12.9, 3.5, 3.0, 2.7, 2.2 Hz), 1.92 (2H,

ddddd, J = 12.9, 10.3, 10.1, 2.5, 2.2 Hz), 1.99 (1H, ddd, J = 13.9, 10.0,

4.0 Hz), 2.15 (2H, ddd, J = 13.9, 3.9, 1.9 Hz), 2.72 (1H, ddd, J = 17.9,

8.5, 6.1 Hz), 4.05 (2H, dd, J = 10.1, 3.6 Hz), 5.51 (1H, t, J = 4.7 Hz); ¹³C

NMR (100 MHz, DMSO‑d₆) δ: 16.2, 22.6, 23.0, 25.3, 27.2, 27.6, 30.7,

31.9, 42.1, 43.5, 49.2, 122.9, 128.8, 136.6, 17.01, 205.0, 210.5; HR-ESI-

MS m/z: calcd for C₁₇H₂₂O₂{[M + H]⁺}258.3610, found 258.1330;

Anal. calcd for C₁₇H₂₂O₂: C, 79.03; H, 8.58; O, 12.38; found: C, 79.00; H,

8.59; O, 12.39%.

C

₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.67; H, 8.81; O,

15.53%.

compound 174, yellow oily liquid, yield 83.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.5 Hz), 1.04–1.29 (4H, 1.07 (td, J = 6.5,

4.5 Hz), 1.12 (h, J = 6.5 Hz), 1.19 (h, J = 6.5 Hz), 1.26 (td, J = 6.5, 4.5

Hz)), 1.41 (1H, dddd, J = 14.1, 10.2, 3.4, 2.8 Hz), 1.63–1.85 (4H, 1.65

(dddd, J = 14.1, 3.1, 2.9, 2.4 Hz), 1.81 (tdtd, J = 4.5, 2.9, 2.8, 2.7 Hz)),

1.99 (1H, ddd, J = 13.5, 2.8, 2.5 Hz), 2.08 (2H, ddd, J = 13.5, 10.2, 2.7

Hz), 2.38 (2H, ddd, J = 13.8, 3.4, 2.4 Hz), 4.05 (2H, dd, J = 10.2, 2.5

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.5, 20.3, 27.3, 31.6, 32.5, 35.8,

36.7, 40.6, 42.0, 48.1, 125.8, 173.5, 197.2, 206.6; HR-ESI-MS m/z: calcd

for C₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1328; Anal. calcd for

compound 180, yellow oily liquid, yield 75.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.46 (2H, ddddd, J = 12.9, 10.3, 10.1, 2.5, 2.2 Hz), 1.79

(2H, dddd, J = 14.1, 10.3, 4.6, 2.7 Hz), 1.93 (2H, dtd, J = 13.6, 10.1,

2.2 Hz), 1.99 (1H, dddd, J = 13.6, 3.6, 3.5, 2.2 Hz), 2.14 (2H, ddd, J =

15.5, 8.5, 6.1 Hz), 3.48 (1H, dd, J = 10.1, 3.6 Hz), 4.05 (2H, dd, J = 4.6,

1.6 Hz), 7.13–7.30 (5H, 7.18 (tt, J = 7.7, 1.3 Hz), 7.24 (dddd, J = 7.8,

7.7, 1.9, 0.5 Hz), 7.29 (dddd, J = 7.8, 1.3, 1.2, 0.5 Hz)); ¹³C NMR (100

MHz, DMSO‑d₆) δ: 23.0, 26.9, 31.8, 41.2, 42.2, 50.8, 64.2, 126.4, 126.7,

127.2, 128.8, 145.8, 170.3, 202.8, 210.5; HR-ESI-MS m/z: calcd for

C

₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.30; H, 9.16; O,

14.53%.

compound 175, yellow oily liquid, yield 82.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.77–0.87 (6H, 0.79 (t, J = 6.5 Hz), 0.86 (d, J = 6.9 Hz),

1.13–1.25 (4H, 1.17 (dq, J = 6.9, 6.5 Hz), 1.23 (dq, J = 6.9, 6.5 Hz)),

1.41 (1H, dddd, J = 14.1, 10.3, 3.4, 2.8 Hz), 1.62 (2H, 1.73 (dddd, J =

14.1, 2.9, 2.8, 2.4 Hz), 1.78–2.00 (4H, 1.81 (ddtd, J = 13.2, 2.9, 2.8, 2.7

Hz), 1.91 (dtt, J = 13.2, 10.3, 2.8 Hz), 2.00 (dtd, J = 13.4, 2.8, 2.5 Hz)),

2.25 (2H, dtd, J = 13.4, 10.2, 2.7 Hz), 4.05 (2H, dd, J = 10.2, 2.5 Hz);

¹³C NMR (100 MHz, DMSO‑d₆) δ: 13.9, 20.5, 23.5, 28.0, 28.8, 29.3,

34.0, 37.7, 37.8, 57.5, 60.2, 122.7, 174.3, 202.7, 207.4; HR-ESI-MS m/z:

calcd for C₁₅H₂₂O₂{[M + H]⁺}234.3390, found 234.1333; Anal. calcd

for C₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found: C, 76.84; H, 9.48; O,

13.67%.

C

₁₇H₁₈O₂{[M + H]⁺}254.3290, found 254.1606; Anal. calcd for

₁₇H₁₈O₂: C, 80.28; H, 7.13; O, 12.58; found: C, 80.25; H, 7.16; O,

12.54%.

compound 181, yellow oily liquid, yield 78.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, t, J = 6.5 Hz), 0.94–1.32 (11H, 1.00 (dddd, J =

14.1, 3.1, 2.9, 2.4 Hz), 1.13 (ddtd, J = 10.3, 2.9, 2.8, 2.7 Hz), 1.16

(dddd, J = 14.1, 10.2, 3.4, 2.8 Hz), 1.20 (dq, J = 12.9, 2.8 Hz), 1.12

(dtd, J = 12.9, 10.3, 2.8 Hz), 1.30 (dtd, J = 12.9, 10.3, 2.8 Hz)),

1.71–1.78 (6H, 1.72 (dq, J = 12.9, 2.8 Hz), 1.76 (ttt, J = 10.3, 4.7, 2.8

Hz)), 1.92 (2H, qt, J = 10.3, 2.8 Hz), 2.00 (1H, ddd, J = 13.5, 2.8, 2.5

Hz), 2.08 (2H, ddd, J = 13.5, 10.2, 2.7 Hz), 2.49 (2H, ddd, J = 14.3, 3.4,

2.4 Hz), 4.05 (2H, dd, J = 10.2, 2.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 14.5, 20.2, 27.4, 30.0, 30.4, 32.9, 33.6, 35.2, 37.7, 37.8, 40.9, 42.4,

50.2, 126.5, 170.1, 204.2, 210.1; HR-ESI-MS m/z: calcd for

compound 176, yellow oily liquid, yield 82.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.84 (9H, s), 1.15–1.33 (3H, 1.19 (dddd, J = 13.6, 3.2, 2.9,

2.6 Hz), 1.30 (dddd, J = 13.6, 10.3, 2.9, 2.4 Hz)), 1.92 (2H, dddd, J =

3.8, 3.2, 2.4, 2.2 Hz), 2.00 (1H, ddd, J = 14.1, 8.9, 3.8 Hz), 2.09 (2H,

ddd, J = 14.1, 5.3, 2.2 Hz), 2.48 (2H, ddd, J = 13.7, 2.9, 2.6 Hz), 4.05

(2H, dd, J = 8.9, 5.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 27.6, 27.8,

32.2, 32.4, 32.5, 36.4, 41.1, 46.3, 47.5, 126.3, 173.5, 206.5, 210.4; HR-

ESI-MS m/z: calcd for C₁₅H₂₂O₂{[M + H]⁺}234.3390, found 234.0757;

Anal. calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found: C, 76.85; H,

9.48; O, 13.66%.

C

₂₀H₃₀O₂{[M + H]⁺}302.4580, found 302.2018; Anal. calcd for

₂₀H₃₀O₂: C, 79.42; H, 10.00; O, 10.58; found: C, 79.39; H, 10.01; O,

10.59%.

compound 182, yellow oily liquid, yield 72.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (1H, dddd, J = 14.1, 3.1, 2.9, 2.4 Hz), 1.25 (1H, dq, J

= 13.0, 2.8 Hz), 1.43 (4H, ddtd, J = 10.3, 2.9, 2.8, 2.7 Hz), 1.65 (4H,

dtd, J = 13.0, 10.3, 2.8 Hz), 1.90 (2H, dtd, J = 13.0, 10.3, 2.8 Hz), 2.01

(1H, ddd, J = 13.5, 2.8, 2.5 Hz), 2.09 (2H, dddd, J = 14.1, 10.2, 3.4, 2.8

Hz), 2.20 (2H, ddd, J = 13.5, 10.2, 2.7 Hz), 2.37 (2H, ddd, J = 14.3, 3.4,

2.4 Hz), 3.84 (4H, ddd, J = 14.6, 5.6, 1.4 Hz),4.05 (2H, dd, J = 10.2, 2.5

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.0, 30.2, 33.1, 33.5, 33.6, 35.0,

37.5, 40.0, 42.6, 50.2, 64.1, 119.0, 126.7, 172.1, 203.4, 211.5; HR-ESI-

MS m/z: calcd for C₁₉H₂₆O₄{[M + H]⁺}318.4130, found 318.2066;

Anal. calcd for C₁₉H₂₆O₄: C, 71.67; H, 8.23; O, 20.10; found: C, 71.62; H,

8.24; O, 20.13%.

compound 177, yellow oily liquid, yield 83.5%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86 (3H, t, J = 6.5 Hz), 1.07–1.44 (9H, 1.08 (tt, J = 6.8,

6.5 Hz), 1.12 (td, J = 6.8, 4.5 Hz), 1.23 (td, J = 6.8, 4.5 Hz), 1.29 (tq, J

= 6.9, 6.5 Hz), 1.41 (tq, J = 6.9, 6.5 Hz)), 1.64 (2H, dddd, J = 14.1, 10.2,

3.4, 2.8 Hz), 1.79 (2H, dddd, J = 14.1, 3.1, 2.9, 2.4 Hz), 2.08 (1H, ddd, J

= 13.5, 10.2, 2.7 Hz), 2.38 (2H, ddd, J = 13.8, 3.4, 2.4 Hz), 2.66 (2H,

ddd, J = 16.3, 6.1, 1.4 Hz), 4.05 (2H, dd, J = 10.2, 2.5 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 14.1, 22.7, 26.3, 27.0, 31.6, 32.3, 33.2, 35.7,

37.0, 40.6, 41.9, 51.6, 125.0, 174.0, 206.6, 207.1; HR-ESI-MS m/z: calcd

for C₁₆H₂₄O₂{[M + H]⁺}248.3660, found 248.1725; Anal. calcd for

C₁₆H₂₄O₂: C, 77.38; H, 9.74; O, 12.88; found: C, 77.34; H, 9.76; O,

12.90%.

compound 183, yellow oily liquid, yield 66.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.28 (2H, ddd, J = 14.1, 2.8, 2.5 Hz), 1.92 (2H, dddd, J =

13.8, 3.1, 2.9, 2.4 Hz), 1.99 (1H, dddd, J = 13.8, 10.2, 3.4, 2.8 Hz), 2.39

(2H, ddd, J = 14.1, 10.2, 2.7 Hz), 2.66 (2H, ddd, J = 14.6, 3.4, 2.4 Hz),

3.59 (1H, ddd, J = 14.6, 10.2, 3.1 Hz), 4.04 (2H, dd, J = 10.2, 2.5 Hz),

7.56–7.70 (4H, 7.62 (ddd, J = 7.8, 1.3, 0.5 Hz), 7.68 (ddd, J = 7.8, 7.6,

1.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 24.9, 32.3, 32.8, 34.4, 41.8,

49.5, 68.3, 123.0, 125.8, 128.3, 134.5, 140.0, 168.1, 202.8, 210.8; HR-

compound 178, yellow oily liquid, yield 81.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.75–0.86 (9H, 0.76 (t, J = 7.1 Hz), 0.85 (q, J = 7.1 Hz)),

1.02 (1H, dddd, J = 14.1, 3.2, 2.9, 2.6 Hz), 1.18 (2H, dddd, J = 14.1,

10.3, 2.9, 2.4 Hz), 1.30 (2H, dddd, J = 3.8, 3.2, 2.4, 2.2 Hz), 1.92 (2H,

ddd, J = 14.1, 5.3, 2.2 Hz), 1.99 (1H, ddd, J = 14.1, 8.9, 3.8 Hz), 2.09

(2H, ddd, J = 17.9, 6.1, 1.4 Hz), 2.48 (2H, ddd, J = 13.7, 10.3, 2.9 Hz),

4.05 (2H, dd, J = 8.9, 5.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 8.5,

25.4, 27.1, 32.5, 32.9, 33.8, 34.7, 36.5, 41.2, 43.5, 50.7, 126.2, 172.6,

197.7, 211.3; HR-ESI-MS m/z: calcd for C₁₆H₂₄O₂{[M + H]⁺}248.3660,

found 248.1561; Anal. calcd for C₁₆H₂₄O₂: C, 77.38; H, 9.74; O, 12.88;

found: C, 77.35; H, 9.74; O, 12.91%.

ESI-MS m/z: calcd for C₁₉H₁₇NO₄{[M

+

H]⁺}323.3480, found

323.2357; Anal. calcd for C₁₉H₁₇NO₄: C, 70.58; H, 5.30; N, 4.33; O,

19.79; found: C, 70.54; H, 5.31; N, 4.35; O, 19.80%.

compound 184, yellow oily liquid, yield 71.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.05–1.20 (2H, 1.09 (dddd, J = 14.1, 3.1, 2.9, 2.4 Hz), 1.18

(dddd, J = 14.1, 10.2, 3.4, 2.8 Hz)), 1.86 (2H, ddd, J = 13.5, 2.8, 2.5

Hz), 2.05 (1H, ddd, J = 13.5, 10.2, 2.7 Hz), 2.28 (2H, ddd, J = 14.4, 3.4,

2.4 Hz), 2.59 (2H, ddd, J = 14.4, 10.2, 3.1 Hz), 2.95 (1H, ddd, J = 16.3,

6.1, 1.4 Hz), 4.45 (2H, dd, J = 10.2, 2.5 Hz), 6.71 (2H, ddd, J = 8.2, 2.6,

0.5 Hz), 7.11 (2H, ddd, J = 8.2, 1.1, 0.5 Hz), 9.23 (1H, s); ¹³C NMR (100

MHz, DMSO‑d₆) δ: 33.1, 33.4, 34.2, 36.4, 41.4, 42.7, 51.0, 115.5, 1278,

compound 179, yellow oily liquid, yield 76.3%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.16–1.54 (10H,1.18 (dddd, J = 14.2, 10.0, 4.7, 4.0 Hz),

1.25 (dtd, J = 13.6, 10.1, 2.2 Hz), 1.36 (dddd, J = 14.1, 10.3, 4.6, 2.7

Hz), 1.41 (dddd, J = 14.1, 3.0, 2.5, 1.6 Hz), 1.50 (dddd, J = 13.6, 3.6,

18

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

128.0, 136.0, 155.8, 172.5, 201.9, 210.9; HR-ESI-MS m/z: calcd for

compound 191, yellow oily liquid, yield 48.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.82–1.02 (9H, 0.88 (d, J = 6.9 Hz), 0.93 (s), 0.98 (s), 1.07

(2H, ddd, J = 16.3, 8.5, 6.2 Hz), 1.61–1.68 (2H, 1.62 (dd, J = 14.1, 2.7

Hz), 1.67 (dd, J = 14.1, 10.3 Hz)), 1.89 (1H, d, J = 14.1 Hz), 2.00 (1H,

ddd, J = 10.2, 6.9, 2.7 Hz), 2.29 (2H, dd, J = 16.3, 6.1, 1.4 Hz), 3.96

(2H, d, J = 10.2 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 23.1, 26.0, 29.6,

32.2, 35.2, 42.1, 44.7, 49.1, 63.3, 126.8, 171.4, 204.0, 210.0; HR-ESI-

MS m/z: calcd for C₁₄H₂₀O₂{[M + H]⁺}220.3120, found 220.1174;

Anal. calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15; O, 14.52; found: C, 76.31; H,

9.16; O, 14.53%.

C

₁₇H₁₈O₃{[M + H]⁺}270.3280, found 270.1093; Anal. calcd for

C₁₇H₁₈O₃: C, 75.53; H, 6.71; O, 17.76; found: C, 75.50; H, 6.72; O,

17.78%.

compound 185, yellow oily liquid, yield 70.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.13–128 (2H, 1.18 (dtt, J = 16.4, 10.3, 2.8 Hz), 1.25

(ddtd, J = 16.4, 2.9, 2.8, 2.7 Hz)), 1.37–1.66 (2H, 1.46 (dddd, J = 13.8,

2.9, 2.8, 2.4 Hz), 1.57 (dtd, J = 13.5, 10.2, 2.7 Hz)), 2.01 (1H, dtd, J =

13.5, 2.8, 2.5 Hz), 2.10 (2H, dddd, J = 13.8, 10.3, 3.4, 2.8 Hz), 2.19 (3H,

s), 2.41 (2H, ddd, J = 16.3, 6.1, 1.4 Hz), 2.68 (1H, ddd, J = 16.7, 8.5,

6.1 Hz), 4.04 (2H, dd, J = 10.2, 2.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆)

δ: 14.4, 23.4, 25.8, 28.6, 33.9, 43.0, 56.5, 60.1, 126.3, 174.9, 207.0,

207.2, 208.5; HR-ESI-MS m/z: calcd for C₁₃H₁₆O₃{[M + H]⁺}220.2680,

found 220.0962; Anal. calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32; O, 21.79;

found: C, 70.85; H, 7.34; O, 21.81%.

compound 192, yellow oily liquid, yield 47.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.85 (3H, d, J = 6.6 Hz), 1.16 (3H, s), 1.83 (2H, ddd, J =

13.5, 3.3, 2.6 Hz), 2.00 (1H, ddd, J = 14.1, 3.5, 1.6 Hz), 2.09 (2H, dddd,

J = 14.1, 10.1, 4.7, 3.4 Hz), 2.45 (1H, ddd, J = 13.5, 10.2, 3.0 Hz), 2.71

(2H, ddd, J = 14.9, 6.0, 1.4 Hz), 4.05 (2H, ddd, J = 14.9, 8.6, 6.1 Hz);

¹³C NMR (100 MHz, DMSO‑d₆) δ: 18.8, 20.2, 22.5, 30.8, 31.7, 33.6,

34.6, 37.2, 51.6, 126.4, 169.2, 200.6, 209.9; HR-ESI-MS m/z: calcd for

C₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.0871; Anal. calcd for

compound 186, yellow oily liquid, yield 66.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (3H, t, J = 7.1 Hz), 1.51–1.80 (6H, 1.51 (dtt, J = 13.5,

10.3, 2.8 Hz), 1.66 (ddtd, J = 13.5, 2.9, 2.8, 2.7 Hz), 1.78 (ddd, J = 16.3,

8.5, 6.2 Hz)), 2.00 (1H, dddd, J = 13.9, 10.3, 3.4, 2.8 Hz), 2.27 (2H, dtd,

J = 13.5, 10.2, 2.7 Hz), 2.96 (1H, dtd, J = 13.5, 2.8, 2.5 Hz), 4.04 (2H,

dd, J = 3.4, 2.4 Hz), 4.16 (2H, q, J = 7.1 Hz); ¹³C NMR (100 MHz,

DMSO‑d₆) δ: 13.9, 14.2, 24.6, 27.0, 33.8, 41.7, 56.9, 59.9, 64.0, 122.8,

169.9, 172.7, 205.6, 209.9; HR-ESI-MS m/z: calcd for C₁₄H₁₈O₄{[M +

H]⁺}250.2940, found 250.0996; Anal. calcd for C₁₄H₁₈O₄: C, 67.18; H,

7.25; O, 25.57; found: C, 67.14; H, 7.26; O, 25.59%.

C

₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.65; H, 8.81; O,

15.54%.

compound 193, yellow oily liquid, yield 50.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.95 (3H, d, J = 6.7 Hz), 1.12–1.37 (4H, 1.25 (ddd, J =

16.3, 8.5, 6.2 Hz), 1.37 (dddd, J = 14.1, 10.3, 3.4, 2.8 Hz)), 1.61–1.81

(2H, 1.68 (dtd, J = 14.2, 10.3, 2.8 Hz), 1.80 (dddd, J = 14.1, 2.9, 2.8,

2.4 Hz)), 1.99 (1H, td, J = 10.2, 2.7 Hz), 2.23–2.44 (3H, 2.24 (ddd, J =

16.3, 6.1, 1.4 Hz), 2.40 (qdd, J = 6.7, 3.4, 2.4 Hz)), 3.89 (2H, ddd, J =

16.6, 6.2, 1.4 Hz),), 4.64–4.74 (2H, 4.65 (d, J = 1.3 Hz), 4.73 (d, J = 1.3

Hz)); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 19.1, 22.4, 28.3, 33.1, 34.2,

41.4, 45.1, 69.3, 115.6.128.0, 156.2, 170.3, 199.7, 210.9; HR-ESI-MS

m/z: calcd for C₁₅H₂₀O₂{[M + H]⁺}232.3230, found 232.1383; Anal.

calcd for C₁₅H₂₀O₂: C, 77.55; H, 8.68; O, 13.77; found: C, 77.51; H, 8.69;

O, 13.80%.

compound 187, yellow oily liquid, yield 58.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.13–1.18 (2H, 1.15 (dddd, J = 14.3, 10.3, 3.4, 2.8 Hz),

1.18 (dtt, J = 13.8, 10.3, 2.8 Hz)), 1.89 (3H, ddd, J = 13.8, 2.9, 2.7 Hz),

1.96 (1H, dddd, J = 14.3, 2.9, 2.8, 2.4 Hz), 2.08 (2H, dtd, J = 13.5, 2.8,

2.5 Hz), 2.38 (2H, dtd, J = 13.5, 10.2, 2.7 Hz), 2.64 (2H, 2.78 (ddd, J =

16.3, 6.1, 1.4 Hz), 4.02 (2H, dd, J = 10.2, 2.5 Hz), 4.57 (1H, dd, J = 3.4,

2.4 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 14.0, 20.6, 27.9, 29.3, 33.6,

37.7, 49.7, 60.2, 123.9, 173.1, 174.5, 206.7, 207.7; HR-ESI-MS m/z:

calcd for C₁₃H₁₇NO₃{[M + H]⁺}235.2830, found 235.0876; Anal. calcd

for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95; O, 20.40; found: C, 66.33; H,

7.29; N, 5.98; O, 20.39%.

compound 194, yellow oily liquid, yield 52.4%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.79–0.97 (9H, 0.84 (d, J = 6.9 Hz), 0.84 (d, J = 6.9 Hz),

0.92 (d, J = 6.9 Hz)), 1.10–1.31 (4H, 1.15 (dtd, J = 14.6, 10.3, 2.8 Hz),

1.26 (dddd, J = 14.1, 10.3, 3.4, 2.8 Hz)), 1.41 (1H, Hdddd, J = 14.6, 2.9,

2.8, 2.7 Hz), 1.61 (1H, dddd, J = 14.1, 2.9, 2.8, 2.4 Hz), 1.80 (1H, tqd, J

= 10.2, 6.9, 2.7 Hz), 2.00 (1H, dd, J = 10.2, 2.7 Hz), 2.53 (2H, ddd, J =

16.3, 6.1, 1.4 Hz), 4.05 (2H, dd, J = 16.3, 8.5, 6.2 Hz); ¹³C NMR (100

MHz, DMSO‑d₆) δ: 14.2, 21.0, 25.8, 28.0, 29.7, 31.2, 31.7, 37.8, 50.5,

56.7, 126.1, 172.6, 204.4, 209.4; HR-ESI-MS m/z: calcd for

compound 188, yellow oily liquid, yield 52.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.15 (9H, s), 1.77 (2H, dddd, J = 14.2, 3.1, 2.9, 2.4 Hz),

2.00 (1H, dddd, J = 14.2, 10.2, 3.4, 2.8 Hz), 2.10 (2H, ddd, J = 14.1,

2.8, 2.5 Hz), 2.38 (2H, ddd, J = 14.1, 10.2, 2.7 Hz), 2.66 (2H, ddd, J =

13.9, 3.4, 2.4 Hz), 3.94–4.07 (3H, 3.94 (dtd, J = 2.9, 2.8, 2.7 Hz), 4.04

(dd, J = 10.2, 2.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 27.9, 28.9,

29.4, 31.6, 33.7, 37.7, 47.5, 60.2, 77.4, 124.0, 156.3, 174.5, 199.6,

207.6; HR-ESI-MS m/z: calcd for C₁₆H₂₃NO₄{[M + H]⁺}293.3630,

found 293.1353; Anal. calcd for C₁₆H₂₃NO₄: C, 65.51; H, 7.90; N, 4.77;

O, 21.81; found: C, 65.48; H, 7.91; N, 4.76; O, 21.85%.

C

₁₅H₂₂O₂{[M + H]⁺}234.3390, found 234.1116; Anal. calcd for

₁₅H₂₂O₂: C, 76.88; H, 9.46; O, 13.65; found: C, 76.84; H, 9.47; O,

13.68%.

compound 195, yellow oily liquid, yield 43.8%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 2.00 (1H, ddd, J = 16.3, 6.1, 1.4 Hz), 2.11 (2H, ddd, J =

13.1, 10.0, 3.8 Hz), 2.19 (2H, ddd, J = 13.1, 4.0, 1.9 Hz), 2.46 (2H, ddd,

J = 14.9, 3.8, 1.9 Hz), 2.71 (2H, ddd, J = 14.9, 10.0, 4.0 Hz), 4.04 (2H,

dd, J = 16.4, 10.3 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 29.9, 31.7,

37.9, 42.5, 45.6, 50.6, 126.1, 172.7, 197.6, 207.0, 210.7; HR-ESI-MS m/

z: calcd for C₁₁H₁₂O₃{[M + H]⁺}192.2140, found 192.0893; Anal. calcd

for C₁₁H₁₂O₃: C, 68.74; H, 6.29; O, 24.97; found: C, 68.70; H, 6.31; O,

24.98%.

compound 189, yellow oily liquid, yield 53.2%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.18 (2H, ddtd, J = 13.4, 2.9, 2.8, 2.7 Hz), 1.91 (2H, dtt, J

= 13.4, 10.3, 2.8 Hz), 1.99 (1H, dddd, J = 14.1, 10.3, 3.4, 2.8 Hz), 2.10

(2H, dtd, J = 13.5, 10.2, 2.7 Hz), 2.36 (2H, dddd, J = 14.1, 2.9, 2.8, 2.4

Hz), 2.66 (1H, dtd, J = 13.5, 2.8, 2.5 Hz), 4.05 (2H, dd, J = 10.2, 2.5

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 20.5, 24.3, 32.9, 37.7, 39.7, 57.0,

65.1, 124.2, 173.3, 205.1, 207.8; HR-ESI-MS m/z: calcd for

C

₁₁H₁₃ClO₂{[M + H]⁺}212.6730, found 212.1360; Anal. calcd for

compound 196, yellow oily liquid, yield 40.1%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.17 (2H, dddd, J = 11.5, 10.2, 3.4, 2.8 Hz), 1.91 (1H,

dddd, J = 11.5, 3.1, 2.9, 2.4 Hz), 1.98 (1H, ddd, J = 14.1, 2.8, 2.5 Hz),

2.10 (2H, ddd, J = 14.1, 10.2, 2.7 Hz), 2.39 (2H, ddd, J = 13.2, 3.4, 2.4

Hz), 2.63 (2H, ddd, J = 13.2, 10.2, 3.1 Hz), 4.04 (1H, dd, J = 10.2, 2.5

Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 28.1, 29.9, 30.7, 31.5, 37.9, 45.2,

49.8, 126.2, 170.7, 194.7, 207.0; HR-ESI-MS m/z: calcd for

₁₁H₁₃ClO₂: C, 62.12; H, 6.16; Cl, 16.67; O, 15.05; found: C, 62.10; H,

6.15; Cl, 16.68; O, 15.07%.

compound 190, yellow oily liquid, yield 50.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.86–1.07 (8H, 0.90 (s), 1.03 (ddd, J = 16.2, 8.5, 6.2 Hz)),

1.48–1.58 (2H, 1.49 (ddd, J = 13.8, 2.8, 2.7 Hz), 1.54 (ddd, J = 13.8,

10.3, 2.9 Hz)), 1.81 (2H, d, J = 14.9 Hz), 2.01 (1H, dtd, J = 13.3, 2.8,

2.5 Hz), 2.66 (2H, dtd, J = 13.3, 10.2, 2.7 Hz), 4.05 (2H, dd, J = 10.2,

2.5 Hz); ¹³C NMR (100 MHz, DMSO‑d₆) δ: 21.1, 25.9, 32.1, 33.5, 38.8,

44.6, 45.1, 49.0, 128.7, 172.7, 203.6, 209.8; HR-ESI-MS m/z: calcd for

C

₁₁H₁₅NO₂{[M + H]⁺}193.2460, found 193.0849; Anal. calcd for

₁₁H₁₅NO₂: C, 68.37; H, 7.82; N, 7.25; O, 16.56; found: C, 68.33; H,

7.83; N, 7.26; O, 16.58%.

C

₁₃H₁₈O₂{[M + H]⁺}206.2850, found 206.0861; Anal. calcd for

compound 197, yellow oily liquid, yield 70.6%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 0.84–1.41 (19H, 0.85 (t, J = 6.5 Hz), 0.95 (dddd, J = 14.1,

3.1, 2.9, 2.4 Hz), 1.16 (ddtd, J = 10.3, 2.9, 2.8, 2.7 Hz), 1.18 (dddd, J =

₁₃H₁₈O₂: C, 75.69; H, 8.80; O, 15.51; found: C, 75.65; H, 8.82; O,

15.53%.

19

S. Zhou et al.

Bioorganic Chemistry 109 (2021) 104701

14.1, 10.2, 3.4, 2.8 Hz), 1.21 (dq, J = 12.9, 2.8 Hz), 1.24 (dtd, J = 12.9,

10.3, 2.8 Hz), 1.26 (dtd, J = 12.9, 10.3, 2.8 Hz), 1.34 (dq, J = 12.9, 2.8

Hz), 1.38 (td, J = 6.8, 4.7 Hz)), 1.64–1.84 (5H, 1.64 (td, J = 6.8, 4.7 Hz),

1.69 (ttt, J = 10.3, 4.7, 2.8 Hz), 1.80 (dtd, J = 12.7, 10.3, 2.8 Hz)), 2.00

(1H, ddd, J = 13.5, 2.8, 2.5 Hz), 2.21 (2H, ddd, J = 13.5, 10.2, 2.7 Hz),

80% and were in the logarithmic growth stage, the cell density was

adjusted after digestion with 0.25% trypsin. 2 × 10⁴cells per hole

vaccination in 96-well culture plate, let stand train for 24 h, will be

randomly divided into groups of cells: normal group, DMSO group

(dimethylsulfoxide, 5‰), positive group group (methotrexate, 1

μM and

2.34 (2H, ddd, J = 14.3, 3.4, 2.4 Hz), 4.05 (2H, dd, J = 10.2, 2.5 Hz); ¹³

C

0.1 μM) , target compounds group (1 μM and 0.1 μM). After the cells

NMR (100 MHz, DMSO‑d₆) δ: 14.5, 23.0, 24.2, 28.4, 29.2, 30.2, 33.1,

33.6, 33.7, 36.2, 37.2, 37.8, 40.9, 42.6, 50.2, 124.7, 168.3, 200.8, 211.6;

HR-ESI-MS m/z: calcd for C₂₁H₃₂O₂{[M + H]⁺}316.4850, found

316.2496; Anal. calcd for C₂₁H₃₂O₂: C, 79.70; H, 10.19; O, 10.11; found:

C, 79.67; H, 10.21; O, 10.13%.

were fully adherent to the wall, the liquid in the pore was discarded. In

addition to the normal group, the equivalent medium was added to the

other groups, and the test substance with corresponding concentration

was added to the other groups (among which the insoluble test sub-

stance could be dissolved in DMSO less than 5‰). After continued cul-

ture for 48 h, centrifuged at 1500 r/min for 15 min and the supernatant

of the cells in each group was collected. The LDH (lactate dehydroge-

nase) activity of each group was determined by the LDH assay kit in

strict accordance with the kit instructions. The LDH activity of each

group was calculated according to the deﬁnition of lactate dehydroge-

compound 198, yellow oily liquid, yield 55.9%; ¹H NMR (400 MHz,

DMSO‑d₆) δ: 1.16 (2H, dddd, J = 14.2, 3.1, 2.9, 2.4 Hz), 1.91 (2H, dddd,

J = 14.2, 10.2, 3.4, 2.8 Hz), 2.09 (1H, ddd, J = 14.1, 2.8, 2.5 Hz), 2.39

(2H, ddd, J = 14.1, 10.2, 2.7 Hz), 2.65 (2H, ddd, J = 13.9, 3.4, 2.4 Hz),

3.44 (1H, ddd, J = 16.7, 6.2, 1.4 Hz), 4.04 (2H, dd, J = 10.2, 2.5 Hz),

5.06 (2H, s), 7.22–7.36 (5H, 7.23 (tt, J = 7.7, 1.3 Hz), 7.31 (dddd, J =

7.8, 1.3, 1.0, 0.6 Hz), 7.35 (dddd, J = 7.8, 7.7, 1.6, 0.6 Hz); ¹³C NMR

(100 MHz, DMSO‑d₆) δ: 28.1, 28.2, 29.8, 31.7, 38.8, 47.4, 60.4, 63.5,

126.9, 127.1, 128.5, 128.8, 136.6, 156.4, 172.9, 207.7, 210.7; HR-ESI-

MS m/z: calcd for C₁₉H₂₁NO₄{[M + H]⁺}327.3800, found 327.1534;

Anal. calcd for C₁₉H₂₁NO₄: C, 69.71; H, 6.47; N, 4.28; O, 19.55; found:

C, 69.68; H, 6.46; N, 4.30; O, 19.58%.

nase, and the calculation formula was LDH activity (U/L) = (OD_measured

OD_control)/(OD_standard- OD_blank) × C × N × 1000.

-

4.5. In vivo anti-rheumatoid arthritis activity test

Adult male rats (200 ± 20 g, SD, SPF, china) were kept under non-

speciﬁc therapeutic conditions, and the animals had free access to

drinking water and food. After 10 days of acclimation, the 0.1 mL of

complete freund’s adjuvant (CFA, USA) was injected 2 cm away from the

rat tail root to cause inﬂammation, and 0.1 mL of normal saline was

injected into the normal group. After 14 days of immunity, when all the

rats showed sign of arthritis, the rats were randomly divided into groups

(positive control group, compound test groups), and the rats injected

with saline acted as the normal group [36]. All test subjects were given

orally once a day at the prescribed dose (normal group and blank control

group were not given, positive control group was given methotrexate of

50 mg/kg, compound groups were given two different doses of 50 mg/

kg and 100 mg/kg), and continuous gavage treatment was performed for

12 days. The test material was prepared with edible vegetable oil as the

solvent, and the speciﬁed concentration was prepared as required for

testing. The paws volume of the rats were measured with a toe volu-

metric meter (SA701, China) after administration on one day and twelve

day. On thirteen day (a day after the last dose), all the experimental rats

were killed and autopsies were performed. The blood samples from the

4.2. In vitro inhibition test of rat synovial cells

When the synovial cells of rats grew to the conﬂuence level of 70%-

80% and were in the logarithmic growth stage, the cell density was

adjusted after digestion with 0.25% trypsin. 5 × 10³cells per hole

vaccination in 96-well culture plate, let stand train for 24 h, will be

randomly divided into groups of cells: normal group, DMSO group

(dimethylsulfoxide), positive group group (methotrexate) , target com-

pound groups. After the cells were fully adherent to the wall, the liquid

in the pore was discarded. In addition to the normal group, the equiv-

alent medium was added to the other groups, and the test substance with

corresponding concentration was added to the other groups (among

which the insoluble test substance could be dissolved in DMSO less than

5‰). After 48 h of continuous culture, the liquid in the wells was dis-

carded, and then 200

μ

L of complete culture medium was added. At the

same time, 20

μ

L CCK8 (cell counting kit-8) solution was added to each

well, and the solution was placed in the cell culture tank for another 4 h

[35]. Finally, optical density (OD) value of each well was measured with

a enzyme-linked immuno sorbent assay (ELISA) at the wavelength of

450 nm, and the cell inhibition rate of each group was calculated. Cell

abdominal aorta were treated and the serum cytokine IL-6 and TNF-

α

were determined by ELISA kit (RAB0307, USA).

inhibition rate = (OD_{normal group}- OD_{administration group})/OD_{normal group}

.

4.6. Acute toxicity (half lethal dose, LD₅₀) test in mice

4.3. In vitro morphological study of rat synovial cells

Pretest: It was taken 14 mice (20 ± 2 g, SPF, china), each group of 2

were divided into 7 groups. The sexes were equally divided, they need to

stop feeding the 4–6 h and hand water freedom before the experiment.

The selection of the different doses of the groups, 0.4 mL of sample so-

lution containing the test substance was given by oral intragastric

administration, and dimethyl sulfoxide (DMSO) was used as blank

control. After giving the drug, fasting 1–2 h, continuous observation 48

h and hand recorded the symptoms and death number. Found the dose of

100% and 0% death of the mice, and used these doses as the highest and

lowest doses of the later test.

When the synovial cells of rats grew to the conﬂuence level of 70%-

80% and were in the logarithmic growth stage, the cell density was

adjusted after digestion with 0.25% trypsin. 5 × 10³cells per hole

vaccination in 96-well culture plate, let stand train for 24 h, will be

randomly divided into groups of cells: normal group, DMSO group

(dimethylsulfoxide, 1

μ

M), positive group group (methotrexate, 1

μM) ,

target compounds group (1

μ

M). After the cells were fully adherent to

the wall, the liquid in the pore was discarded. In addition to the normal

group, the equivalent medium was added to the other groups, and the

test substance with corresponding concentration was added to the other

groups (among which the insoluble test substance could be dissolved in

DMSO less than 5‰). After 48 h of continuous culture, it were placed on

the cell imaging analysis system to observe the morphological changes

of synovial cells in each group.

Formal test: The 100% and 0% lethal doses obtained in the pretest

was converted into common logarithm. The maximum lethal dose and

the minimum lethal dose was used for the common logarithmic differ-

ence, and according to the equidistant dose group divide into 6 groups.

Each dose group used 10 mice, the sexes are equally divided. Before the

experiment, it was necessary to stop feeding the 4–6 h and hand water

freedom. Each mice was given a 0.4 mL of sample solution containing

the test substance, and used as a blank control for the DMSO. After

giving the test, fasting 1–2 h hand normal feeding, observed the death

rate, death time and poisoning phenomenon of the mice in 14 days.

4.4. In vitro LDH release test of rat synovial cells

When the synovial cells of rats grew to the conﬂuence level of 70%-

20

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Bioorganic Chemistry 109 (2021) 104701

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4.7. Docking simulation

The surﬂex-dock a semi-ﬂexible of molecular dock method, it was

employed to estimate the interaction between Toll-like receptor 4

(TLR4) and representative active the compounds [33]. The surﬂex-dock

employs protomol, an idealized ensemble of CH4, NH and CO probes, to

guide the generation of docking conformers of the ligands. Herein,

crystal structures of the TLR4-MD-2 dimer in complex with co-

crystalized antagonist Eritoran (PDB ID: 3FXI) was used for molecular

docking. Before docking, all the ligands were charged by tripos force

ﬁeld with the conjugate gradient minimizer. The maximum iteration

step and energy gradient were set to 10 000 times and 0.05 kcal/mol⋅Å,

respectively. In surﬂex-dock, the protomol was generated based on the

residues within the 8 Å distance from co-crystalized antagonist eritoran.

The search grid and the number of additional starting conformations

were set as 2 Å and 3 Å, respectively. The self-scoring, molecule frag-

mentation, soft grid, pre- and post-dock minimizations were considered

in the docking processes. Total score, which indicates -log (K_D) was used

for ligand ranking. Ultimately, the lowest energy conformation was

utilized to analyze the binding modes between TLR4 and the represen-

tative compounds. The conformer with the lowest binding energy was

further analyzed using PyMOL molecular graphics system.

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Declaration of Competing Interest

[18] Y. Zhang, L. Zhang, Y. Zhang, J.J. Xu, L.L. Sun, S.Z. Li, The protective role of

liquiritin in high fructose-induced myocardial ﬁbrosis via inhibiting NF-kappaB

and MAPK signaling pathway. Biomed. Pharmacother, 84 (2016) 1337-1349.

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The authors declare that they have no known competing ﬁnancial

interests or personal relationships that could have appeared to inﬂuence

the work reported in this paper.

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cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in

vivo, Int. J. Oncol. 51 (2017) 1383 –1394 .

Acknowledgements

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The Project was Sponsored by the National Natural Science Foun-

dation of China (21662012, 41866005). The Project was also Sponsored

by Chongqing University Students’ Training Project of Innovation and

Undertaking (201510637085), Doctoral Program of Chongqing Normal

University (No.12XLB006), and Outstanding Achievements Trans-

formation Project in Chongqing Normal University (No.15XZH08), and

the Postgraduate Research and Innovation Project of Hainan Normal

University (Hsyx2018-8) and Open Foundation Project of Key Labora-

tory of Tropical Medicinal Resource Chemistry of Ministry of Education

(RDZH2019002).

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22

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Design, synthesis and anti-rheumatoid arthritis evaluation of double-ring conjugated enones

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