Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

Article abstract of DOI:10.1080/14756366.2019.1690481

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide–streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.

Full text of DOI:10.1080/14756366.2019.1690481

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Design and synthesis of tricyclic terpenoid
derivatives as novel PTP1B inhibitors with
improved pharmacological property and in vivo
antihyperglycaemic efficacy
Lingling Yang, Feng Chen, Cheng Gao, Jiabao Chen, Junyan Li, Siyan Liu,
Yuanyuan Zhang, Zhouyu Wang & Shan Qian
To cite this article: Lingling Yang, Feng Chen, Cheng Gao, Jiabao Chen, Junyan Li, Siyan
Liu, Yuanyuan Zhang, Zhouyu Wang & Shan Qian (2020) Design and synthesis of tricyclic
terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo
antihyperglycaemic efficacy, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 152-164,
DOI: 10.1080/14756366.2019.1690481
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2020, VOL. 35, NO. 1, 152–164
https://doi.org/10.1080/14756366.2019.1690481
RESEARCH PAPER
Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors
with improved pharmacological property and in vivo antihyperglycaemic efficacy
Lingling Yanga, Feng Chena, Cheng Gaoa, Jiabao Chena, Junyan Lia, Siyan Liua, Yuanyuan Zhangb, Zhouyu Wangb
and Shan Qiana
b
aDepartment of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, China; Department of Chemistry,
College of Science, Xihua University, Chengdu, China
ABSTRACT
ARTICLE HISTORY
Received 4 September 2019
Revised 15 October 2019
Accepted 30 October 2019
Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and
clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibi-
tory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity.
Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate
the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and
34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma
HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties
can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating
effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide–strep-
tozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular
architectures and antihyperglycaemic activity could be developed in the treatment of T2D.
KEYWORDS
Protein tyrosine
phosphatase 1B; oleanolic
acid; insulin-resistant;
antihyperglycaemic effect;
type 2 diabetes
GRAPHICAL ABSTRACT
1. Introduction
development of diabetes18, cancer19, hepatic fibrosis20, bacterial
infection21, rheumatoid arthritis22 and hypertension23. Many
PTP1B inhibitors have been reported, but the discovery of
PTP1B inhibitors with superior cell permeability and in vivo
potency is difficult and so far there is no PTP1B inhibitors
The predominant pathophysiological factor of type 2 diabetes
(T2D) is insulin resistance1–4
. Though many anti-T2D drugs
have emerged in the past decade5,6, traditional anti-T2D agents
such as repaglinide, metformin, dipeptidyl peptidase-IV inhibitors,
a-glucosidase inhibitors and glucagon-like peptide-1 agonists, and
thiazolidinediones are still the most efficacious oral drugs in the
first-line monotherapy of T2D7. It is undoubted that new insulin
entered III phase clinical trial18,24
.
Hundreds of natural products have been isolated and identified
as PTP1B inhibitors, and natural products with interesting struc-
tural diversity have potential to develop the new PTP1B inhibi-
sensitisers will meet great needs of T2D patients8,9
.
tors25–27
. In our previous work, some oleanolic acid (OA)
Protein tyrosine phosphatase 1B (PTP1B) dephosphosphory-
lates the tyrosine-phosphorylated insulin receptor (IR) and the
downstream insulin receptor substrate (IRS) to down regulate
derivatives with modified A-ring, C-ring, and C17 moiety were
designed and synthesized28–33. Within these OA derivatives, com-
pound C10a (Figure 1) exhibited the most PTP1B inhibition (IC50:
3.12 lM), which was 7.6-fold more than the parent compound
OA28. However, the triterpenoid derivative C10a has too large
molecular weight (>500) and some pharmacological defects, such
as weak cell permeability, poor bioavailability and improper lipid/
water partition coefficient. C10a also showed the considerable
cytotoxicity. Therefore, the structure of C10a needs to be opti-
mised to develop the potent PTP1B inhibitors with favourable
insulin transduction10–15
. PTP1B inhibitors could potentially
improve insulin sensitivity and normalise glucose levels and
therefore could be a promising therapeutic strategy in the T2D
patients. Recent studies also identified the involvement of intra-
islet PTP1B in the regulation of insulin release and reinforce
the potential of PTP1B inhibitors for the treatment of beta-cell
secretory failure in the pathogenesis of T2D16,17
.
Besides,
PTP1B-mediated dephosphorylation has been implicated in the pharmacological properties.
CONTACT Shan Qian
China; Zhouyu Wang
qians33@163.com
zhouyuwang77@gmail.com
Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu 610039,
Department of Chemistry, College of Science, Xihua University, Chengdu 610039, China.
Supplemental data for this article can be accessed here.
ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
153
The structural optimisation strategy is shown in Figure 2. The
structure of C10a contains hydrophobic scaffold, linker and aryl
moiety. As displayed in Figure 3(A,B), the molecular docking has
demonstrated the hydrophobic interactions between the terpen-
oid scaffold of C10a and the surrounding amino residues of
PTP1B are critical for the complex stability, but the pentacyclic
core of C10a is too complicated. We assumed this scaffold could
be simplified to the smaller tricyclic fragment containing the same
stereo-conformation of fused A/B ring junction, such as the tricyc-
lic terpenoid scaffold of compound 15 as shown in Figure 3(C).
One of the methyl group at 4-position also was retained, because
it was beneficial for interaction with Arg2428, which is an import-
ant residue at the second site of PTP1B for substrate specificity
(the second site of PTP1B is a noncatalytic cleft-like binding
pocket, which is not conserved among all PTPs)35. As shown in
Figure 3(C), C ring was replaced with the substituted benzene
ring, which could provide opportunities to form more
Figure 1. The chemical structures of OA and lead compound C10a.
Figure 2. The structural optimisation strategy.
Figure 3. C10a and 15 docked in the PTP1B active site (PDB ID: 2B0734). (A) Only the active site was shown, displaying the protein in surface representation and ligand
C10a in stick representation; (B) C10a, Coloured green and displayed in stick representation, bound to these important residues in the interior of the active site. All hydro-
gen atoms are omitted for clarity; (C) 15 bound to the important residues in the interior of the active site; (D) The overlapping docking modes of C10a and 15.

154
L. YANG ET AL.
hydrophobic and p–p interactions. D ring and E ring were simpli- (6a–b)39. Finally, ester 6a was saponified with aq.NaOH to give
fied to the linker from C ring to the aryl moiety. Insertion of polar
group (e.g. carboxyl, ether) into this linker would be beneficial for
the favourable balance between hydrophilicity and hydrophobi-
city. The overlapping figure of C10a and 15 indicated these com-
pounds have similar docking modes with amino residues of PTP1B
(Figure 3(D)). Only two hydrogen-bond interactions between C10a
and PTP1B were observed (Tyr46 and Lys120), so the aryl moiety
of C10a was replaced with various substituted rings in order to
enhance inhibition, since the aryl moiety was important for the
substrate recognition19.
acid 7.
A couple of methyl groups at 4-position is most frequently
found in the terpenoid scaffold. As shown in Scheme 2, the con-
version of the COOH at 4-position to CH3 was also investigated.
Acids 1 and 2 were firstly esterified by treatment with EtI and
K2CO3 to give corresponding esters, which were subsequently
reduced to afford alcohols. Conversion of alcohols to its tosylates
in pyridine proceeded in satisfactory yield. Zn/NaI reduction40 of
abietane-tosylates afforded dienes 11–12 in satisfactory yield,
respectively. Then, diene 12 was oxidative rearranged with SeO2
to obtain alcohol 13, which was converted to phenol 14 by
hydroperoxide rearrangement.
2. Results and discussion
The final products 15–34 were synthesised via nucleophilic
substitution of 6 b and corresponding tosylate or alkyl bromide,
and subsequent deprotection of O-protected intermediates
(Scheme 3(A–C)). As shown in Scheme 3(A), the tosylate inter-
mediates of 15–19 and 25–34 were provided from corresponding
alcohols, which were synthesised via condensation of the acids
with different rings and diols with different length in the presence
of DCC/DMAP. As shown in Scheme 3(B), the tosylate intermedi-
ates of 20–23 were provided from corresponding alcohols, which
were synthesised via nucleophilic substitution. As shown in
Scheme 3(C), the alkyl bromide intermediate of 24 was synthes-
ised from the phenol and bromoacetyl bromide in alka-
line condition.
2.1. Chemistry
The synthesis procedure to achieve 15-hydroxydehydroabietic acid
(3) from abietic acid (AA) involved addition, elimination, and oxi-
dation. However, according to the literatures36–38, alcohol 3 was
obtained in only 10% yield in our laboratory. We therefore
improved the synthetic method and 3 was finally obtained in 70%
overall yield (Scheme 1). According to the improved synthetic pro-
cedure, AA (1) was treated with 33% HBr/AcOH and the resulting
8, 15-dibromo derivative was heated in the presence of LiOH/DMF
to afford diene (2), with four methyl groups of all singlets by
1HNMR. Oxidative rearrangement of 2 with SeO2 provided 15-
hydroxydehydroabietate (3) in 80% yield. 3 was esterified by treat-
ment with EtI (or BnBr) to give ester 4a (4 b). 4a was then
reduced with LiAlH4 to give alcohol 5. We found 15-hydroxydehy-
droabietic derivatives are not suitable synthesis intermediates
because of high steric hindrance of C-15 position, and thus hydro-
peroxide rearrangement of esters 4a–b with t-BuOOH and H2SO4/
2.2. Enzymatic hPTP1B inhibitory activities and SAR analysis
As shown in Table 1, the PTP1B inhibitory activities of abietic
derivatives with two types of terpenoid scaffolds (A and B) were
AcOH gave the 13-hydroxy-8,11,13-podocarpatriene derivatives firstly evaluated. Structure–activity relationship (SAR) was also
Scheme 1. Synthesis of the compounds 2–7.
Scheme 2. Synthesis of the compounds 8–14.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
155
(A)
(B)
(C)
Scheme 3. Synthesis of the compounds 15–34.
discussed. The carboxyl group at 4-position was beneficial for
PTP1B inhibition. Esterification of the carboxyl group to give corre-
sponding ethyl ester (3 vs 4a), or reduction to the corresponding
alcohol (1 vs 9, 3 vs 5) all resulted in loss of activity. Replacing
the carboxyl group at 4-position with methyl group resulted in
significant drop in activity (1 vs 11). Besides, transformation of
hydroxy isopropyl group at 13-position of 8,11,13-podocarpatriene
derivatives (scaffold B) to hydroxy group (3 vs 7, 13 vs 14)
resulted in loss of activity.
Table 1. The PTP1B inhibitory activities of abietic derivatives 1–14.
(A)
(B)
Cpd.
terpenoid scaffold
X
Y
Inh%@10 lMa
Among tricyclic derivatives 15–34, the compounds 15 (2.9 lM),
28 (4.8 lM) and 34 (8.2 lM) exhibited the most PTP1B enzymatic
inhibitory activities, which were equal to that of the lead com-
pound C10a (3.1 lM), and they have smaller molecular weight
(Table 2). SAR analysis demonstrated that the derivatives with dif-
ferent linker between terpenoid scaffold and ring moiety dis-
played different PTP1B inhibition activity. The inhibitory activity of
PTP1B decreased along with an increase of the length of linker
(15 > 16 > 17). Also, the structure of the linker influenced PTP1B
inhibition. Compared with 20 and 24, 15 displayed higher PTP1B
1
3
4a
5
7
A
B
B
B
B
A
A
A
B
B
COOH
COOH
COOEt
CH2OH
COOH
CH2OH
CH2OTs
CH3
C(CH3)2
C(CH3)2OH
C(CH3)2OH
C(CH3)2OH
OH
C(CH3)2
C(CH3)2
C(CH3)2
C(CH3)2OH
OH
35
19
4
0
1
3
2
0
22
15
9
10
11
13
14
CH3
CH3
aThese experiments were performed in triplicate.

156
L. YANG ET AL.
Table 2. The PTP1B inhibitory activities of tricyclic derivatives 15–34.
Cpd.
X
Linker
Ring
Inh%@10µMa IC50 (µM) SDb
15
COOH
91
7
2.9 0.12
-
16
COOH
17
18
19
20
21
22
23
24
25
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
4
46
57
9
-
-
-
-
1
-
11
49
2
-
-
-
25
26.2 2.50
26
27
COOH
COOH
44
35
-
-
28
29
30
31
COOH
COOH
COOH
COOH
90
1
4.8 0.15
-
-
1
3
-
32
33
COOH
COOH
-4
0
-
-
34
COOH
73
95
8.2 2.10
3.1 0.14
C10a
-
aThese experiments were performed in triplicate.
bSD: standard deviation.
inhibitory activity. Besides, the derivatives containing a benzene our data demonstrated these compounds with tricyclic diterpene
or naphthalene at the ring moiety (15, 18–19, 25–28 and 34)
showed higher inhibitory activity relative to the analogues bearing
the heteroaromatic ring (29) or alicyclic ring (31–33). At the ring
moiety, a clear preference was identified for the polar groups,
with an increase in activity for the carboxyl group (15 and 34)
and amino group (28), whereas substitution with carboxylmethyl
group (30) led to significant loss of activity. The benzene ring
with a carboxyl group at the o-position (15) increased the potency
moiety are potent PTP1B inhibitors.
2.3. Cellular glucose uptake in insulin-resistant HepG2 cells
To assess the insulin sensitisation, the cellular effect of these com-
pounds on insulin-resistant human hepatoma HepG2 cells was
performed. The concentration of insulin and induction time were
relative to those at the p-position (18) or m-position (19). Overall, screened to induce insulin resistance in HepG2 cells according to

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
157
Figure 4. The effect of the compounds on glucose consumption in insulin-resistant HepG2 cells. (A) The HepG2 cells were induced with different concentrations of
insulin; (B) The HepG2 cells were induced for different induction times; (C) HepG2 cells were induced with 1.5ꢀ 10ꢁ5 mmol of insulin for 36h to afford insulin-resistant
cells, and then treated with rosiglitazone (Y group) or the compounds for 24h. After incubation, glucose content in the culture medium was measured by glucose oxi-
dase method. M group: insulin-resistant HepG2 cells without rosiglitazone and the compounds; K group: HepG2 cells without induction by insulin.
Table 3. Pharmaceutical properties of 15, 25 and C10a.
TPSA
Cpd.
MW
HB donors
HB acceptors
cLog P
Rotatable bonds
(Å2)
GI absorption
P-gp substrate
Cytotoxicity
15
25
C10a
466
422
588
2
1
1
7
5
5
4.23
4.68
7.32
8
7
5
110.13
72.83
80.67
High
High
Low
Yes
Yes
No
Low
Low
High
cLog P: consensus log of the octanol/water partition coefficient; GI absorption: gastrointestinal absorption; MW: molecular weight; TPSA: topological polar sur-
face area.
the reported method41,42 with some modification. As shown in (>2 ꢀ 10ꢁ5 mmol) of insulin inhibited cell growth, and microscopic
Figure 4(A), treatment with above 1 ꢀ 10ꢁ5 mmol of insulin examination revealed atrophy of the cells. As shown in
reduced glucose uptake, whereas treatment with 6 ꢀ 10ꢁ6 mmol Figure 4(B), insulin resistance was induced in HepG2 cells at 36 h,
of insulin enhanced glucose uptake. Insulin resistance can be obvi- and rosiglitazone can decrease the insulin resistance. The cell
ously observed when the HepG2 cells were treatment with growth was accelerated after 36 h and insulin resistance was
1.5 ꢀ 10ꢁ5 mmol of insulin, and an insulin sensitiser (rosiglitazone) decreased along with induction time. Therefore, the cells were
can significantly decrease the insulin resistance and improve treated with 1.5 ꢀ 1 0 ꢁ5 mmol of insulin for 36 h to induce the
the glucose uptake. Treatment with higher concentration insulin resistance and produce the most obvious difference of

158
L. YANG ET AL.
Figure 5. The antihyperglycaemic effect in NIDDM mice (n ¼ 8). (A) Diminution of plasmatic glucose concentration over NIDDM mice treated with 15, 25, C10a and
rosiglitazone, respectively; (B) The acute antidiabetic effect of 25 were observed with respect to positive control. M group: NIDDM mice were treated with saline alone.
Y group: NIDDM mice were treated with rosiglitazone.
glucose consumption between insulin resistance group (M group)
and rosiglitazone group (Y group).
3. Conclusions
In this article, a series of tricyclic derivatives containing various
hydrophobic scaffold, linker and aryl moiety were designed and
synthesised from 13-hydroxy-8,11,13-podocarpatriene, and their
inhibitory activity against the PTP1B enzyme was assessed. Among
these compounds, some tricyclic derivatives were described as
potent inhibitors of PTP1B. Compound 25 showed the most effect
on glucose consumption in insulin-resistant HepG2 cells.
Moreover, 25 showed the most antihyperglycemic effect in
NIDDM mice. The therapeutic potential of PTP1B inhibition, as
well as the insulin sensitising and in vivo antihyperglycemic effect
of these compounds, made this discovery an important
opportunity.
As shown in Figure 4(C), most compounds can enhance the
glucose consumption in insulin-resistant HepG2 cells, and the
insulin stimulatory effects on glucose uptake were similar to that
of C10a, but inferior to that of rosiglitazone. Cell viability was
evaluated with the MTT assay and the result demonstrated that
the cytotoxicities of most compounds were acceptable, while
C10a showed the considerable cytotoxicity (see Figure 1S,
Supplementary material). Compared with 15, which exhibited the
most PTP1B enzymatic inhibitory potency, compound 25 has
lower PTP1B inhibition (26.2 lM), but it can more significantly
increase insulin-stimulated glucose uptake in cellular assay. This
result was unsurprising, because most active site-directed PTP1B
inhibitors are phosphotyrosine mimetics with weak cell permeabil-
ity43. We have previously reported that there is a trade-off
between enzymatic inhibition and cell permeability18. We calcu-
lated the pharmaceutical properties of 15, 25 and C10a using the
Swiss ADME. As shown in Table 3, the MW and cLogP value of
C10a are too large, as well as the HB acceptors of 15. Both of
these compounds could not fulfil Lipinski Rule44. 25 fulfilled
Lipinski Rule of Five and has the lowest TPSA, which means more
acceptable oral absorption and cell permeability. These results
demonstrated in silico preferable pharmaceutical properties of 25
were beneficial for its cellular effect.
4. Experimental section
4.1. Chemistry
1H NMR spectra were recorded on a Bruker Avance 400 spectrom-
eter. 13C NMR spectra were recorded on a Bruker DPX 300 spec-
trometer. TMS was the internal standard. Chemical shifts as d
values were recorded in ppm and coupling constants as J values
were recorded in Hz. HRMS spectra were recorded on
a
micrOTOF-Q II 10203 spectrometer. TLC were performed on the
HSGF254 silica gel and UV detection at 254 nm and 365 nm, and
appropriate chromogenic agents.
2.4. The antihyperglycaemic effect in NIDDM mice
The antihyperglycaemic effect of the compounds 15, 25 and C10a
were evaluated on non-insulin dependent diabetes mellitus
4.1.1. Synthesis of abieta-8(9),13(15)-dien-18-oic acid (2)
(NIDDM) mice. Nicotinamide and streptozotocin were adminis- To a solution of 1 (20.00 g, 66.40 mmol) in 64 ml of HOAc was
trated intraperitoneally to induce hyperglycaemia and the plasma added to 33% HBr/HOAc (64 ml). The mixture was stirred at rt for
glucose of mice raised over 4.5 mmol/L45. Rosiglitazone has not 6 h, and then was filtered and the filter cake was washed with
shown effect during the first hour, but it showed the significant HOAc, dried in vacuum overnight to give corresponding crude
antihyperglycaemic effect after 1 h (Figure 5(A,B)). Though C10a dibromo derivative. To a solution of the crude 8,15-dibromo
showed the antihyperglycaemic effect, some mice treated with derivative was added LiOH (2.64 g, 64.72 mmol) in 200 ml of DMF,
C10a appeared the hydroabdomen, thrombus and tail necrosis, and the mixture was stirred at 80 ꢂC for 7 h. Solvent was removed
suggesting the acute toxicity of C10a. Compared with 15, 25 under reduced pressure, and the pH was adjusted to 3 with HCl
showed in vivo antihyperglycaemic effect, correlating with insulin- (aq) and concentrated to give a brown oil 2 without further
resistant cell assay.
purification.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
159
4.1.2.
rearrangement
General
procedure
1:
SeO2-mediated
oxidative
1-Hydroxylmethyl-15-hydroxydehydroabietate (5). Colourless oil;
1H NMR (400 MHz, d6-DMSO) d 12.17 (br, 1H), 8.99 (br, 1H), 7.03 (d,
J ¼ 8.6 Hz, 1H), 6.53 (dd, J ¼ 8.5, 2.5 Hz, 1H), 6.37 (d, J ¼ 2.4 Hz, 1H),
4.12 (br, 1H), 3.17 (d, J ¼ 2.0 Hz, 2H), 2.73–2.67 (m, 2H), 2.25 (d,
J ¼ 12.4 Hz, 1H), 2.00 (dd, J ¼ 12.3, 1.6 Hz, 1H), 1.75–1.55 (m, 8H),
1.38–1.24 (m, 4H), 1.15 (s, 3H), 1.09 (s, 3H). 13C NMR (300 MHz, d6-
DMSO) d 179.9, 155.0, 140.5, 135.8, 125.5, 114.9, 113.6, 53.7, 49.0,
46.7, 45.3, 38.4, 36.7, 36.5, 30.0, 25.4, 21.6, 18.6, 16.7, 14.4. HRMS
(AP-ESI) Calcd. for C20H31O2: 303.2246 [M þ Na]þ. Found: 303.2221.
1-Hydroxymethylabietane (9). Yellow solid; mp: 125–126 ꢂC;
1HNMR (400 MHz, CDCl3) d 5.81 (s, 1H), 5.49–5.42 (m, 1H), 4.25 (s,
1H), 3.54–3.45 (m, 2H), 2.37–1.92 (m, 6H), 1.91–1.77 (m, 4H),
1.67–1.52 (m, 5H), 1.53–1.40 (m, 4H), 1.34–1.26 (m, 6H), 1.26–1.20
(s, 3H), 1.20–1.15 (m, 6H), 1.09–0.98 (m, 8H), 0.98–0.86 (m, 11H),
0.81 (s, 4H). 13C NMR (300 MHz, CDCl3) d 146.0, 145.9, 134.7, 124.9,
124.1, 121.9, 75.7, 72.4, 48.3, 44.5, 37.8, 36.9, 36.7, 31.6, 30.2, 25.0,
21.7, 19.5, 14.2. HRMS (AP-ESI) Calcd. for C20H33O: 289.2526
[M þ Na]þ. Found: 289.2531.
To a solution of 1 equiv. diene in 10 ml/mmol of dry THF was
added 4 equiv. SeO2, and the mixture was stirred at 0 ꢂC for 5 h
under an atmosphere of Ar. The solid was removed by filtration,
and the filtrate was extracted with EtOAc. Solvent was removed
under reduced pressure, and the resulting residue was purified by
flash column chromatography to give product.
15-Hydroxydehydroabieta-18-oic acid (3). Yellow oil; mp:
92–93 ꢂC; 1H NMR (400 MHz, CDCl3) d 7.24 (m, 2H), 7.18 (s, 1H),
2.96 (m, 1H), 2.43–2.00 (m, 3H), 1.92–1.85 (m, 2H), 1.85–1.77 (m,
2H),1.77–1.70 (s, 3H), 1.58 (s, 6H), 1.46 (s, 3H), 1.31 (s, 3H). 13C
NMR (300 MHz, CDCl3): d 184.5, 147.8, 145.9, 134.7, 124.9, 124.1,
121.9, 120.2, 72.4, 60.4, 47.3, 44.5, 37.8, 36.9, 36.7, 31.6, 30.1, 25.0,
18.5, 16.2. HRMS (AP-ESI) Calcd. For C20H28NaO3: 339.2038
[M þ Na]þ. Found: 339.2087.
15-Hydroxydehydroabietane (13). Yellow oil; 1H NMR (400 MHz,
CDCl3) d 7.80 (d, J ¼ 8.2 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H), 7.22 (s,
1H), 5.32 (s, 1H), 3.85 (d, J ¼ 9.3 Hz, 1H), 3.62 (d, J ¼ 9.4 Hz, 1H),
2.93–2.73 (m, 2H), 2.48 (s, 3H), 1.71 (m, 2H), 1.60 (s, 3H), 1.58
(s, 3H), 1.51–1.30 (m, 6H), 1.20 (s, 3H), 0.91 (s, 3H). 13C NMR
4.1.5. General procedure 4: t-BuOOH-mediated hydroperoxide
rearrangement
(300 MHz, CDCl3)
d 129.8, 127.9, 124.8, 124.2, 121.9, 77.6,
To a solution of 1 equiv. ester 5 in 5 ml/mmol AcOH was added 3
equiv. t-BuOOH followed by addition of 0.1 equiv. H2SO4. The mix-
ture was stirred at 50 ꢂC for 1 h. The mixture was diluted with
water and the aqueous phase was extracted with DCM. The
organic phase was washed with Na2CO3 (aq), water and dried.
Solvent was removed under reduced pressure, and the resulting
residue was purified by flash column chromatography to furnish
the product.
Ethyl 13-hydroxy-8,11,13-podocarpatriene-1-carboxylate (6a).
White solid; mp: 96–97 ꢂC; 1H NMR (400 MHz, CDCl3) d 7.12 (d,
J ¼ 8.6 Hz, 1H), 6.66 (dd, J ¼ 8.5, 2.6 Hz, 1H), 6.53 (d, J ¼ 2.4 Hz, 1H),
5.25 (br, 1H), 4.35–3.96 (m, 2H), 2.85 (dd, J ¼ 10.8, 5.2 Hz, 2H),
2.44–2.17 (m, 2H), 1.90–1.62 (m, 7H), 1.29–1.24 (m, 6H), 1.21 (s,
3H). 13C NMR (300 MHz, CDCl3) d 178.8, 153.2, 142.0, 136.6, 125.5,
114.8, 113.1, 60.6, 47.4, 44.9, 38.1, 36.5, 30.1, 25.2, 23.6, 21.5, 18.6,
16.4, 14.2. ESI-MS: 303.1 [M þ H]þ.
72.2, 43.5, 38.0, 37.3, 37.1, 35.0, 31.6, 29.9, 21.6, 18.8, 18.3, 17.1.
HRMS (AP-ESI) Calcd. for C20H30NaO: 309.2195 [M þ Na]þ.
Found: 309.2185.
4.1.3. General procedure 2: K2CO3-mediated esterification
To a solution of 1 equiv. abieta-18-oic acid in acetone was added
3 equiv. K2CO3, and the mixture was stirred for 15 min. The solu-
tion was dropwise added 2 equiv. EtI (for 4a and 8) or BnBr (for
4 b) and the mixture was stirred at 60 ꢂC for 3 h. The mixture was
extracted with EtOAc. Solvent was removed under reduced pres-
sure, and the resulting residue was purified by flash column chro-
matography to give product.
Ethyl 15-hydroxydehydroabietate (4a). Yellow solid; mp:
51–52 ꢂC; 1H NMR (400 MHz, CDCl3) d 7.26 (s, 2H), 7.19 (s, 1H),
4.11–4.18 (m, 2H), 3.05–2.61 (m, 2H), 2.44–2.25 (m, 2H), 1.91–1.83
(m, 2H), 1.83–1.70 (m, 3H),1.31–1.27 (m, 5H), 1.26 (s, 3H), 1.24 (s,
3H). 13C NMR (300 MHz, CDCl3) d 178.4, 147.8, 145.9, 134.6, 126.8,
124.8, 124.1, 121.9, 72.1, 60.4, 47.3, 44.6, 37.8, 36.9, 36.4, 31.5, 30.2,
29.6, 25.0, 23.9, 21.5, 18.5, 16.4, 14.1. HRMS (AP-ESI) Calcd. for
C22H32KO3: 283.1988 [M þ K]þ. Found: 383.1933.
Benzyl 13-hydroxy-8,11,13-podocarpatriene-1-carboxylate (6 b).
White solid; mp: 102–103 ꢂC; 1H NMR (400 MHz, CDCl3) d 9.26 (s,
H),7.44–7.31 (m, 6H), 7.27–7.16 (m, 2H), 2.88–2.78 (m, 2H),
2.35–2.20 (m, 2H), 1.85 –1.67 (m, 2H), 1.58 (s, 3H), 1.23 (d,
J ¼ 3.3 Hz, 3H). 13C NMR (300 MHz, CDCl3) d 178.5, 153.1, 142.0,
136.6, 136.3, 128.5, 128.1, 128.1, 125.6, 114.9, 113.1, 66.4, 47.7,
45.0, 38.1, 36.4, 36.5, 30.0, 25.3, 21.5, 18.6, 16.6. HRMS (AP-ESI)
Calcd. for C24H29O3: 365.2111 [M þ H]þ. Found: 365.2119.
13-Hydroxy-8,11,13-podocarpatriene (14). Yellow solid. mp:
145–146 ꢂC; 1H NMR (400 MHz, CDCl3) d 7.14 (d, J ¼ 8.6 Hz, 1H),
6.64 (dd, J ¼ 8.5, 2.7 Hz, 1H), 6.53 (d, J ¼ 2.6 Hz, 1H), 4.77 (s, 1H),
3.02–2.65 (m, 2H), 1.88 (m, 1H)1.81–1.56 (m, 4H), 1.54–1.33 (m,
2H), 1.33–1.23 (m, 2H),1.19 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H). 13C
NMR (300 MHz, CDCl3) d 148.1, 138.1, 132.2, 120.9, 110.1, 108.2,
45.8, 37.0, 34.3, 32.6, 28.7, 28.6, 25.7, 20.2, 16.9, 14.6, 14.3. HRMS
(AP-ESI) Calcd. for C17H25O: 245.1878 [M þ H]þ. Found: 245.1895.
Benzyl 15-hydroxydehydroabietate (4 b). Yellow solid; mp:
112–113 ꢂC; 1HNMR (400 MHz, CDCl3)
d 7.42–7.31 (m, 1H),
7.26–7.15 (m, 1H), 7.06–7.00 (m, 1H), 6.89 (s, 1H), 5.19 (dd,
J ¼ 12.4, 3.4 Hz, 2H), 5.10 (s, 1H), 5.07 (s, 1H), 2.91–2.75 (m, 1H),
2.36–2.25 (m, 1H), 1.86–1.61 (m, 2H), 1.33–1.31 (m, 1H), 1.29 (s,
1H), 1.24 (dd, J ¼ 6.4, 3.8 Hz, 1H). 13C NMR (300 MHz, CDCl3) d
177.9, 146.9, 145.7, 136.1, 134.7, 128.9, 127.6, 127.1, 124.9, 124.3,
123.0, 73.9, 67.0, 51.8, 43.8, 38.4, 37.6, 31.6, 30.0, 28.3, 24.7, 20.1,
19.7. HRMS (AP-ESI) Calcd. for C27H35O3: 407.2581 [M þ H]þ.
Found: 407.2585.
4.1.4. General procedure 3: LiAlH4- participated reduction
To a suspension of 4 equiv. LiAlH4 in THF was added 1 equiv.
ester in 10 ml/mmol of THF at 0 ꢂC. The mixture was stirred at rt
for 3 h, and then was quenched by addition of aq.NaOH. The
resulting solid was filtered off. Solvent of the filtrate was removed
under reduced pressure, and the resulting residue was purified by
flash column chromatography to give product.
4.1.6. Synthesis of 13-hydroxy-8,11,13-podocarpatriene-1-carbox-
ylic acid (7)
To a solution of 6 (0.10 g, 0.33 mmol) in 4 ml EtOH/H2O (1:1) was
added NaOH (13.1 mg, 0.99 mmol), and the mixture was stirred at
100 ꢂC for 2 h. The mixture was cooled to rt and pH was adjusted
to 6 with HCl(aq). The resulting solid was filtered off to give the
product 7 (82.5 mg, 91%) as a white solid. mp: 101–102 ꢂC; 1H

160
L. YANG ET AL.
NMR (400 MHz, d6-DMSO) d 12.17 (br, 1H), 8.99 (br, 1H), 7.03 (d, and dried. Solvent was removed under reduced pressure, and the
J ¼ 8.6 Hz, 1H), 6.51 (dd, J ¼ 8.5, 2.5 Hz, 1H), 6.38 (d, J ¼ 2.4 Hz, 1H),
resulting residue was purified by flash column chromatography to
furnish the product.
2.82–2.60 (m, 1H), 2.25 (d, J ¼ 12.4 Hz, 1H), 2.00 (dd, J ¼ 12.3,
1.6 Hz, 1H), 1.78–1.67 (m, 2H), 1.67–1.56 (m, 2H), 1.56–1.45 (m, 2H),
1.44–1.18 (m, 2H), 1.16 (s, 3H), 1.10 (s, 3H). 13C NMR (300 MHz, d6-
4.1.11. General procedure 9: Pd/C-catalyzed hydrogenolysis of the
DMSO) d 180.0, 155.1, 140.5, 135.9, 125.5, 115.0, 113.6, 46.8, 45.4,
40.6, 39.3, 36.5, 30.1, 25.5, 21.6, 18.7, 16.8. HRMS (AP-ESI) Calcd. O-protected group
for C17H22NaO3: 297.1467 [M þ Na]þ. Found: 297.1461.
Pd/C (10%, 1 mg/mg) was added to the solution of 1 equiv. benzyl
ester in 10 ml/mmol of methanol. The mixture was hydrogenolised
under 1 MPa at rt for 12 h. The reaction mixture was filtered.
Solvent of the filtrate was removed under reduced pressure, and
the resulting residue was purified by flash column chromatog-
raphy to furnish the product.
4.1.7. General procedure 5: TsCl-participated sulfonylation
The solution of 1 equiv. alcohol and 5 equiv. tolylsulfonyl chloride
in 3 ml/mmol of pyridine was stirred at rt for 6 h. After removal of
solvent by evaporation, the mixture was dissolved in DCM, fol-
lowed by washed and dried. The mixture was then concentrated
and subjected to flash column chromatography to furnish
the product.
1-Hydroxymethyl-abietane-p-methylbenzenesulfonate (10). White
solid; mp:67–68 ꢂC; 1H NMR (400 MHz, CDCl3) d 7.74–7.66 (d, 2H),
7.40–7.51 (d, 2H),5.81 (s, 1H), 5.58–5.34 (m, 1H), 2.53 (s,
3H),2.32–1.94 (m, 4H), 1.93–1.77 (m, 2H), 1.67–1.54 (m, 3H),
1.50–1.42 (m, 1H), 1.34–1.16 (m, 6H), 1.03 (dd, J ¼ 6.8, 4.0 Hz, 6H),
0.94 (q, J ¼ 6.5 Hz, 3H), 0.92–0.84 (m, 3H). 13C NMR (300 MHz,
CDCl3) d 146.0, 144.4, 140.4, 133.5, 130.5, 128.3, 122.4, 121.3, 73.1,
51.7, 51.1, 39.5, 37.0, 35.4, 34.9, 27.7, 24.2, 22.7, 21.0, 20.3, 18.4,
14.7. HRMS (AP-ESI) Calcd. for C27H39O3S: 443.2614 [M þ H]þ.
Found: 443.2619.
Compound 15. White solid; mp: 72–73 ꢂC; 1HNMR (400 MHz,
CDCl3) d 7.91 (d, J ¼ 7.0 Hz, 1H), 7.67 (d, J ¼ 7.1 Hz, 1H), 7.63–7.44
(m, 2H), 7.12 (t, J ¼ 8.8 Hz, 1H), 6.73 (dd, J ¼ 8.5, 1.9 Hz, 1H), 6.58 (s,
1H), 4.64 (s, 2H), 4.23 (s, 1H), 4.15 (q, J ¼ 7.1 Hz, 1H), 2.84 (d,
J ¼ 5.4 Hz, 2H), 2.35–2.11 (m, 2H), 2.08 (s, 1H), 1.92–1.65 (m, 6H),
1.29 (t, J ¼ 7.1 Hz, 5H), 1.19 (d, J ¼ 7.4 Hz, 3H). 13C NMR (300 MHz,
CDCl3) d 185.4, 179.8, 173.7, 171.3, 156.1, 142.4, 136.3, 130.9,
129.9, 128.8, 125.5, 125.4, 115.0, 114.1, 113.1, 112.9, 65.5, 60.5,
47.4, 44.7, 38.0, 36.6, 30.2, 25.2, 21.7, 18.5, 16.2, 14.2. HRMS (AP-
ESI) Calcd. for C27H29O7: 465.1919 [M – H]ꢁ. Found: 465.1921.
Compound 16. White solid; mp: 109–110 ꢂC; 1HNMR (400 MHz,
CDCl3) d 7.92 (d, J ¼ 6.8 Hz, 1H), 7.70 (d, J ¼ 7.1 Hz, 1H), 7.59 (dt,
J ¼ 13.2, 7.2 Hz, 2H), 7.14 (d, J ¼ 8.7 Hz, 1H), 6.71 (dd, J ¼ 8.6, 2.8 Hz,
1H), 6.56 (dd, J ¼ 11.1, 2.6 Hz, 1H), 5.32 (s, 2H), 4.64 (dd, J ¼ 5.8,
2.8 Hz, 1H), 4.52 (t, J ¼ 6.3 Hz, 1H), 4.29 (d, J ¼ 5.2 Hz, 1H), 4.06 (t,
J ¼ 6.1 Hz, 1H), 4.00 (t, J ¼ 6.2 Hz, 1H), 2.86 (s, 3H), 2.25 (dd,
J ¼ 30.0, 10.2 Hz, 4H), 2.11–2.02 (m, 1H), 1.91–1.78 (m, 4H),
1.78–1.68 (m, 3H), 1.35–1.24 (m, 5H), 1.20 (s, 3H).13C NMR
(300 MHz, CDCl3) d 185.6, 172.5, 168.2, 142.0, 136.3, 133.5, 132.3,
130.8, 129.9, 129.9, 128.7, 125.3, 113.9, 112.7, 64.2, 63.0, 47.5, 44.7,
38.0, 36.7, 36.6, 30.2, 28.4, 25.2, 21.7, 18.5, 16.2. HRMS (AP-ESI)
Calcd. for C28H31O7: 479.2075 [M – H]ꢁ. Found: 479.2070.
4.1.8. General procedure 6: Zn/NaI-mediated reduction
The solution of 1 equiv. p-toluenesulfonate, 10 equiv. zinc and 5
equiv. sodium iodide in 10 ml/mmol of HMPA was stirred at
105 ꢂC for 7 h. The mixture was dissolved in water and the aque-
ous layer was extracted with EtOAc. The combined organic layers
were washed with brine and dried. Solvent was removed under
reduced pressure, and the resulting residue was purified by flash
column chromatography to furnish the product.
7-Isopropyl-1,1,4-trimethyl-decahydrophenanthrene (11). White
oil;1H NMR (400 MHz, CDCl3) d 5.81 (s, 1H), 5.58–5.34 (m, 1H),
2.32–1.94 (m, 2H), 1.93–1.77 (m, 2H), 1.67–1.54 (m, 3H), 1.50–1.42
(m, 1H), 1.34–1.16 (m, 6H), 1.03 (dd, J ¼ 6.8, 4.0 Hz, 6H), 0.94 (q,
J ¼ 6.5 Hz, 3H), 0.92–0.84 (m, 3H), 0.81 (s, 3H). 13C NMR (300 MHz,
d6-DMSO) d 142.6, 137.5, 123.5, 120.6, 52.2, 50.4, 41.8, 40.4, 39.6,
35.05, 33.5, 31.6, 22.7, 20.8, 19.1, 18.4, 15.2, 14.3. HRMS (AP-ESI)
Calcd. for C20H31: 271.2426 [M – H]ꢁ. Found: 271.2242.
Compound 17. White solid; mp: 113–114 ꢂC; 1HNMR (400 MHz,
CDCl3) d 7.69 (d, J ¼ 6.2 Hz, 1H), 7.57 (d, J ¼ 4.8 Hz, 2H), 7.12 (t,
J ¼ 9.5 Hz, 2H), 6.67 (dd, J ¼ 21.8, 7.4 Hz, 2H), 6.52 (d, J ¼ 19.8 Hz,
2H), 4.40 (s, 1H), 3.95 (s, 1H), 2.84 (s, 3H), 2.25 (dd, J ¼ 26.4,
12.1 Hz, 4H), 1.97–1.67 (m, 12H), 1.29 (s, 6H), 1.20 (s, 6H). 13C NMR
(300 MHz, CDCl3) d 156.4, 141.9, 136.6, 136.3, 131.9, 130.9, 128.7,
125.5, 125.3, 115.0, 113.9, 113.1, 112.6, 67.1, 65.7, 47.4, 44.8, 38.1,
36.8, 36.6, 30.0, 25.2, 25.2, 21.7, 18.5, 16.2. HRMS (AP-ESI) Calcd.
for C28H33O7: 493.2232 [M – H]ꢁ. Found: 493.2226.
Compound 18. White solid; mp: 112–113 ꢂC; 1HNMR (400 MHz,
CDCl3) d 8.12 (dt, J ¼ 21.5, 10.8 Hz, 1H), 7.13 (d, J ¼ 8.6 Hz, 1H), 6.65
(dd, J ¼ 8.6, 2.4 Hz, 1H), 6.52 (d, J ¼ 2.4 Hz, 1H), 5.33 (s, 1H), 4.70
(dd, J ¼ 8.9, 4.3 Hz, 1H), 4.33 (t, J ¼ 4.3 Hz, 1H), 2.96–2.79 (m, 2H),
2.34–2.17 (m, 2H), 1.93–1.80 (m, 3H), 1.80–1.70 (m, 2H), 1.54 (q,
J ¼ 6.9 Hz, 2H), 1.31 (s, 3H), 1.22 (d, J ¼ 6.7 Hz, 3H). 13C NMR
(300 MHz, CDCl3) d 185.0, 165.7, 156.1, 153.1, 142.0, 136.6, 130.1,
129.8, 125.5, 115.0, 114.4, 113.1, 112.7, 65.8, 64.2, 47.4, 44.7, 38.1,
36.7, 36.6, 30.0, 25.2, 21.7, 18.5, 16.2. HRMS (AP-ESI) Calcd. for
C27H29O7: 465.1919 [M – H]ꢁ. Found: 465.1928.
4.1.9. General procedure 7: DCC-promoted condensation
To a solution of 1 equiv. carboxylic acid in 1.5 equiv. diol was
added to a solution of 1.5 equiv. DCC and 0.05 equiv. DMAP in
5 ml/mmol of acetonitrile. The mixture was stirred at 0 ꢂC for 1 h,
then transferred to rt and stirred for 5 h. The mixture was
extracted with EtOAc. The combined organic layers were washed
with brine and dried. Solvent was removed under reduced pres-
sure, and the resulting residue was purified by flash column chro-
matography to furnish the product.
Compound 19. White solid; mp: 113–114 ꢂC; 1HNMR (400 MHz,
d6-DMSO) d 8.50 (s, 1H), 8.20 (d, J ¼ 7.6 Hz, 1H), 8.14 (d, J ¼ 7.6 Hz,
1H), 7.65 (t, J ¼ 7.7 Hz, 1H), 7.16 (d, J ¼ 8.7 Hz, 1H), 6.75 (dd, J ¼ 8.6,
2.1 Hz, 1H), 6.63 (s, 1H), 4.62 (s, 2H), 4.30 (s, 2H), 2.87–2.66 (m, 3H),
2.28 (d, J ¼ 12.4 Hz, 1H), 2.01 (d, J ¼ 11.7 Hz, 1H), 1.45–1.19 (m, 4H),
1.16 (s, 3H), 1.1 (s, 3H). 13 C NMR (300 MHz, CDCl3) d 183.0, 169.7,
165.1, 153.1, 142.0, 136.6, 130.1, 129.8, 125.5, 118.0, 117.4, 116.1,
4.1.10. General procedure 8: K2CO3-mediated nucleophilic
substitution
A solution of 3 equiv. ester in 2 ml/mmol of DMF was added to a
solution of 1 equiv. 6b and 5 equiv. K2CO3 in 2 ml/mmol of DMF.
The mixture was stirred at 80 ꢂC for 5 h. The mixture was extracted
with EtOAc. The combined organic layers were washed with brine 115.7, 65.8, 64.2, 47.4, 45.7, 38.1, 36.7, 36.6, 30.0, 29.2, 28.7, 24.7,

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
161
19.7. HRMS (AP-ESI) Calcd. for C27H29O7: 465.1919 [M – H]ꢁ. 30.2, 26.9, 25.2, 21.7, 18.5, 16.2. HRMS: m/z calcd for C26H30O5
[M þ H]þ 424.2166, found 224.2199.
Found: 465.1926.
Compound 20. White solid; mp: 102–103 ꢂC; 1HNMR (400 MHz,
CDCl3) d 8.21 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.63–7.51 (m, 1H), 7.21–7.03
(m, 3H), 6.78 (dd, J ¼ 8.6, 2.5 Hz, 1H), 6.63 (d, J ¼ 2.3 Hz, 1H),
4.63–4.51 (m, 2H), 4.42–4.30 (m, 2H), 3.01–2.78 (m, 3H), 2.27 (dd,
J ¼ 31.5, 12.4 Hz, 3H), 1.95–1.81 (m, 4H), 1.81–1.70 (s, 3H), 1.28 (d,
J ¼ 13.2 Hz, 4H), 1.24–1.16 (m, 4H). 13 C NMR (300 MHz, CDCl3) d
184.8, 166.0, 157.3, 155.5, 143.0, 136.6, 134.9, 133.9, 125.6, 122.7,
118.5, 114.2, 113.4, 112.7, 68.5, 65.3, 47.4, 44.7, 38.0, 36.7, 30.2,
25.2, 21.6, 18.5, 16.2. HRMS: m/z calcd for C26H31O6 [M þ H]þ
439.2115, found 439.2123.
Compound 26. White solid; mp: 111–112 ꢂC; 1H NMR (400 MHz,
CDCl3) d 10.69 (s, 1H), 7.86 (dd, J ¼ 8.0, 1.7 Hz, 1H), 7.51–7.43 (m,
1H), 7.19 (d, J ¼ 8.7 Hz, 1H), 7.00 (d, J ¼ 7.7 Hz, 1H), 6.92–6.85 (m,
1H), 6.77 (dd, J ¼ 8.7, 2.7 Hz, 1H), 6.63 (d, J ¼ 2.7 Hz, 1H), 4.74–4.63
(m, 2H), 4.33–4.26 (m, 2H), 2.31 (d, J ¼ 12.7 Hz, 1H), 2.23 (dd,
J ¼ 12.4, 1.9 Hz, 1H), 1.97–1.68 (m, 5H), 1.60–1.41 (m,3H), 1.31 (s,
3H), 1.22 (s, 3H). 13C NMR (300 MHz, CDCl3) d 184.8, 170.0, 161.7,
156.1, 142.6, 136.5, 135.9, 130.2, 125.5, 119.2, 117.6, 114.3, 112.8,
112.3, 65.7, 63.8, 60.4, 47.4, 44.7, 38.1, 36.8, 36.7, 30.2, 25.2, 21.7,
18.5, 16.2. HRMS: m/z calcd for C26H30O6 [M þ H]þ 440.2115,
found 440.2146.
Compound 21. White solid; mp: 112–113 ꢂC; 1HNMR (400 MHz,
CDCl3) d 8.19 (dd, J ¼ 7.8, 1.7 Hz, 1H), 7.62–7.52 (m, 1H), 7.20–7.03
(m, 3H), 6.77 (dd, J ¼ 8.7, 2.6 Hz, 1H), 6.61 (d, J ¼ 2.5 Hz, 1H), 5.32
(s, 1H), 4.44 (t, J ¼ 6.0 Hz, 2H), 4.17 (t, J ¼ 5.4 Hz, 2H), 2.97–2.84 (m,
3H), 2.43–2.34 (m, 2H), 2.30 (d, J ¼ 12.6 Hz, 1H), 2.23 (d, J ¼ 12.3 Hz,
1H), 1.92–1.80 (m, 4H), 1.80–1.69 (m, 3H),1.54–1.28 (m, 3H),1.25 (s,
3H),1.25 (s, 3H). 13 C NMR (300 MHz, CDCl3) d 184.9, 166.3, 157.7,
156.1, 142.4, 136.4, 135.0, 133.8, 125.5, 122.0, 117.8, 113.8, 112.7,
112.4, 67.5, 64.5, 47.4, 44.7, 38.1, 36.7, 36.6, 30.2, 29.1, 25.2, 21.6,
18.5, 16.2. HRMS: m/z calcd for C27H33O6 [M þ H]þ 453.2272,
found 453.2286.
Compound 27. White solid; mp: 128–129 ꢂC; 1H NMR (400 MHz,
CDCl3) d 8.09–8.06 (m, 1H), 7.58 (t, J ¼ 7.9 Hz, 1H), 7.48–7.43 (m,
1H), 7.19 (d, J ¼ 8.8 Hz, 1H), 6.78 (dd, J ¼ 8.7, 2.8 Hz, 1H), 6.66–6.64
(m, 1H), 4.67 (t, J ¼ 9.2 Hz, 1H), 4.30 (t, J ¼ 9.2 Hz, 1H), 1.90–1.83
(m, 4H), 1.83–1.73 (m, 3H),1.66–1.42 (m, 3H), 1.31 (s, 3H), 1.22 (s,
3H). 13 C NMR (300 MHz, CDCl3) d 183.0, 166.0, 154.2, 140.5, 134.5,
133.3, 131.4, 130.0, 126.8, 113.8, 111.4, 66.4, 63.9, 51.5, 43.9, 38.4,
37.6, 37.4, 30.1, 28.1, 24.7, 20.1, 19.7. HRMS: m/z calcd for
C26H29ClO5 [M þ H]þ 457.1776, found 457.1774.
Compound 28. White solid; mp: 126–127 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.88 (dd, J ¼ 8.1, 1.4 Hz, 1H), 7.33–7.25 (m, 1H), 7.18 (d,
J ¼ 8.7 Hz, 1H), 6.77 (dd, J ¼ 8.7, 2.7 Hz, 1H), 6.71–6.60 (m, 3H), 4.62
(t, J ¼ 9.6, 2H), 4.28 (t, J ¼ 9.6, 2H), 3.01–2.83 (m, 2H), 2.36–2.18 (m,
2H), 1.96–1.82 (m, 4H), 1.82–1.73 (m, 2H), 1.31 (s, 3H), 1.22 (s, 3H).
13 C NMR (300 MHz, CDCl3) d 168.0, 156.2, 150.5, 142.4, 136.4,
134.2, 131.5, 125.4, 116.7, 116.3, 114.3, 112.8, 110.6, 66.0, 62.9,
47.4, 44.8, 38.1, 36.8, 36.7, 30.2, 25.2, 21.7, 18.5, 16.2. HRMS: m/z
calcd for C26H31NO5 [M þ H]þ 439.2275, found 439.2271.
Compound 22. White solid; mp: 156–157 ꢂC; 1HNMR (400 MHz,
CDCl3) d 7.96–7.90 (m, 1H), 7.76–7.68 (m, 1H), 7.60 (tt, J ¼ 13.6,
6.8 Hz, 2H), 5.27 (dd, J ¼ 25.2, 11.3 Hz, 2H), 4.39 (d, J ¼ 11.0 Hz, 1H),
3.92 (d, J ¼ 11.1 Hz, 1H), 2.96 (d, J ¼ 29.7 Hz, 1H), 2.64–2.50 (m, 1H),
2.40 (dd, J ¼ 6.5, 3.5 Hz, 1H), 2.36 (dd, J ¼ 6.4, 3.5 Hz, 1H), 2.15–2.07
(m, 1H), 2.02–1.87 (m, 6H), 1.77 (dt, J ¼ 13.0, 8.3 Hz, 3H), 1.69–1.60
(m, 2H), 1.45 (s, 4H), 1.29 (t, J ¼ 12.0 Hz, 5H), 1.23–1.15 (m, 6H). 13 C
NMR (300 MHz, CDCl3) d 185.2, 171.8, 158.7, 156.1, 142.5, 136.5,
130.6, 129.6, 125.4, 123.0, 121.2, 115.2, 114.3, 112.7, 66.8, 66.3,
53.4, 47.4, 44.7, 38.1, 36.6, 30.2, 25.2, 21.7, 18.5, 16.2. HRMS: m/z
calcd for C26H31O6 [M þ H]þ 439.2115, found 439.2120.
Compound 29. White solid; mp: 158–159 ꢂC; 1H NMR (400 MHz,
CDCl3) d 8.79 (d, J ¼ 4.7 Hz, 1H), 8.14 (d, J ¼ 7.8 Hz, 1H), 7.86 (t,
J ¼ 7.8 Hz, 1H), 7.56–7.47 (m, 1H), 7.16 (d, J ¼ 8.8 Hz, 1H), 6.74 (s,
1H), 6.61 (d, J ¼ 7.9 Hz, 1H), 4.76 (t, J ¼ 9.2 Hz, 1H), 4.33 (t,
J ¼ 9.2 Hz, 1H), 3.01–2.83 (m, 2H), 2.36–2.18 (m, 2H), 1.95–1.83 (m,
4H), 1.83–1.70 (m, 2H), 1.31 (s, 3H), 1.22 (s, 3H). 13 C NMR
(300 MHz, CDCl3) d 168.7, 155.9, 142.7, 136.5, 125.5, 114.2, 112.6,
65.4, 64.6, 56.4, 53.5, 47.3, 44.8, 43.8, 38.2, 36.8, 36.7, 30.2, 25.7,
25.2, 21.7, 18.6, 16.4. HRMS: m/z calcd for C25H29NO5 [M þ H]þ
424.2118, found 424.2115.
Compound 23. White solid; mp: 158–159 ꢂC; 1HNMR (400 MHz,
CDCl3) d 7.74 (d, J ¼ 7.6 Hz, 1H), 7.68 (s, 1H), 7.40 (t, J ¼ 7.9 Hz, 1H),
7.25–7.16 (m, 2H), 6.82–6.76 (m, 1H), 6.65 (s, 1H), 5.33 (s, 1H), 4.36
(dd, J ¼ 13.3, 3.8 Hz, 3H), 3.02–2.83 (m, 2H), 2.29 (dd, J ¼ 23.2,
12.4 Hz, 2H), 1.87 (dd, J ¼ 21.6, 11.8 Hz, 2H), 1.77 (t, J ¼ 11.0 Hz,
2H), 1.57 (dd, J ¼ 12.7, 6.6 Hz, 1H), 1.48–1.32 (s, 3H), 1.32–1.25 (s,
3H). 13 C NMR (300 MHz, CDCl3) d 185.2, 171.8, 158.7, 156.1, 142.5,
136.5, 130.6, 129.6, 125.4, 123.0, 121.2, 115.2, 114.3, 112.7, 66.8,
66.3, 47.4, 44.7, 38.1, 36.7, 30.2, 25.2, 21.7, 18.5, 16.2. HRMS: m/z
calcd for C26H31O6 [M þ H]þ 439.2115, found 439.2118.
Compound 30. White solid; mp: 161–162 ꢂC; 1H NMR (400 MHz,
CDCl3) d 8.04 (d, J ¼ 8.7 Hz, 1H), 7.52 (t, J ¼ 7.5 Hz, 1H), 7.38 (t,
J ¼ 7.3 Hz, 1H), 7.30 (d, J ¼ 8.4 Hz, 1H), 7.16 (d, J ¼ 8.8 Hz, 1H), 6.75
(dd, J ¼ 8.7, 2.6 Hz, 1H), 6.61 (d, J ¼ 2.5 Hz, 1H), 4.68–4.61 (m, 2H),
4.33–4.22 (m, 2H), 4.06 (s, 2H), 2.94–2.70 (m, 2H), 2.29 (d,
J ¼ 12.5 Hz, 1H), 2.20 (d, J ¼ 13.9 Hz, 1H), 1.94–1.84 (m, 2H),
1.84–1.68 (m, 3H), 1.60–1.41 (m, 2H), 1.28 (s, 3H), 1.20 (s, 3H). 13 C
NMR (300 MHz, CDCl3) d 185.1, 177.0, 167.3, 156.1, 142.5, 136.4,
135.4, 132.8, 132.4 131.3, 129.4 127.7, 125.4, 114.2, 112.8, 65.7,
63.8, 47.4, 44.7, 40.7, 38.1, 36.7, 36.6, 30.1, 25.2, 21.6, 18.5, 16.2.
Compound 24. Yellow oil; mp: 145–146 ꢂC; 1H NMR (400 MHz,
CDCl3) d 8.21 (dd, J ¼ 7.8, 1.8 Hz, 1H), 7.67–7.56 (m, 1H), 7.28 (t,
J ¼ 4.4 Hz, 1H), 7.22 (t, J ¼ 7.2 Hz, 1H), 7.04 (d, J ¼ 8.3 Hz, 1H), 6.92
(dd, J ¼ 8.6, 2.5 Hz, 1H), 6.83 (d, J ¼ 2.5 Hz, 1H), 5.06 (s, 2H),
1.85–1.76 (m, 2H),1.76–1.68 (m, 2H),1.68–1.62 (m, 2H), 1.66–1.40
(m, 3H), 1.31 (s, 3H), 1.23 (s, 3H). 13 C NMR (300 MHz, CDCl3) d
184.6, 166.5, 166.1, 156.5, 147.8, 147.3, 137.0, 134.9, 134.1, 125.7,
123.1, 120.9, 119.0, 118.2, 113.1, 66.4, 47.30, 44.3, 37.9, 37.1, 36.7,
29.9, 25.1, 21.4, 18.4, 16.2. HRMS: m/z calcd for C26H28O7 [M þ H]þ
454.1908, found 454.1902.
HRMS: m/z calcd for C28H32O7 [M þ Na]þ
504.2221,
found 504.2071
Compound 31. White solid; mp: 116–117 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.15 (d, J ¼ 8.8 Hz, 1H), 6.71 (dd, J ¼ 8.7, 2.6 Hz, 1H), 6.57
(s, 1H), 4.48–4.31 (m, 2H), 4.20–3.89 (m, 2H), 3.03–2.73 (m, 4H),
2.25 (dd, J ¼ 32.2, 11.8 Hz, 2H), 2.04 (s, 1H), 1.88–1.82 (m, 2H),
1.82–1.76 (m, 2H), 1.76–1.71 (m, 2H), 1.55–1.36 (m, 5H), 1.28 (s,
3H), 1.20 (s, 3H). 13 C NMR (300 MHz, CDCl3) d 185.1, 179.9, 173.6,
156.1, 142.4, 136.3, 125.3, 114.3, 114.2, 112.8, 112.7, 65.8, 63.0,
Compound 25. White solid; mp: 138–139 ꢂC; 1H NMR (400 MHz,
CDCl3) d 8.13–8.05 (m, 1H), 7.59 (t, J ¼ 7.4 Hz, 1H), 7.46 (t,
J ¼ 7.7 Hz, 1H), 7.19 (d, J ¼ 8.7 Hz, 1H), 6.78 (dd, J ¼ 8.7, 2.6 Hz, 1H),
6.64 (d, J ¼ 2.5 Hz, 1H), 4.67 (t, J ¼ 9.2 Hz, 1H), 4.30 (t, J ¼ 9.6 Hz,
1H), 3.04–2.83 (m, 2H), 2.39–2.14 (m, 2H), 1.95–1.69 (m, 5H),
1.65–1.48 (m, 2H), 1.31 (s, 3H), 1.23 (s, 3H). 13 C NMR (300 MHz,
CDCl3) d 185.0, 166.6, 156.2, 142.4, 136.5, 133.1, 129.9, 129.8,
128.4, 125.4, 125.4, 114.2, 112.7, 65.9, 63.6, 47.4, 44.7, 38.1, 36.7, 60.4, 47.3, 44.7, 42.5, 42.4, 38.1, 36.7, 36.6, 30.1, 25.2, 21.6, 21.1,

162
L. YANG ET AL.
18.5, 16.2, 14.2. HRMS: m/z calcd for C27H36O7 [M þ H]þ 474.2534, glucose concentration is expressed as AX/A0 ꢀ 5.55 mmol/L (AX:
found 474.2570.
OD value of sample; A0: OD value of glucose standard solution).
Compound 32. White solid; mp: 109–110 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.15 (d, J ¼ 8.7 Hz, 1H), 6.69 (d, J ¼ 6.9 Hz, 1H), 6.55 (s,
1H), 4.54 (s, 2H), 4.15 (s, 2H), 3.51 (s, 1H), 2.84 (s, 2H), 2.37–1.89
(m, 5H), 1.75 (m, 6H), 1.59–1.36 (m, 3H), 1.28 (s, 3H), 1.18 (s, 3H).
13 C NMR (300 MHz, CDCl3) d 168.7, 155.9, 142.7, 136.5, 125.5,
114.2, 112.6, 65.4, 64.6, 56.4, 53.5, 47.3, 44.8, 43.8, 38.2, 36.8, 36.7,
30.2, 25.7, 25.2, 21.7, 18.6, 16.4. HRMS: m/z calcd for C24H33NO5
[M þ H]þ 417.2431, found 417.2462.
4.2.3. Animal experiment
During the experiment, the male Kunming mice with 25–30 g
body weight were fasted but received water prior to induction of
diabetes. 110 mg/kg of nicotinamide and 65 mg/kg of streptozoto-
cin (Macklin in Biochemical Technology Co., Ltd., Shanghai, China)
were dissolved in pH 4.5 citrate buffer and intraperitoneally
administrated to induce NIDDM mice model. The mice were intra-
Compound 33. White solid; mp: 48–49 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.16 (d, J ¼ 10.0 Hz, 1H), 6.72 (d, J ¼ 8.6 Hz, 1H), 6.58 (s,
1H), 4.39–3.66 (m, 6H), 3.34–3.29 (m, 2H), 2.99–2.78 (m, 2H),
2.38–2.05 (m, 4H), 1.80–1.63 (m, 4H), 1.54–1.38 (m, 2H), 1.26 (s,
3H), 1.20 (s, 2H). 13C NMR (300 MHz, CDCl3) d 183.4, 156.2, 142.6,
136.5, 125.4, 114.2, 112.5, 69.1, 61.4, 53.1, 47.3, 45.8, 44.9, 38.2,
36.8, 36.7, 30.2, 25.2, 21.6, 18.6, 16.4. HRMS: m/z calcd for
C25H35NO5 [M þ H]þ 431.2588, found 431.2615.
peritoneally administered with
a compound or rosiglitazone
(100 mg/kg) dissolved in saline containing 1% DMSO and 10%
Tween 80. Hyperglycaemia was confirmed by a plasma glucose
increase of more than 4.5 mmol/L measured by a blood glucose
metre (Sinocare GA-3, Changsha, China). Glucose concentrations
from the tail of the mice were measured at 0, 0.5, 1, 2, 3 and 4 h
by the blood glucose metre. Calculate the percentage of blood
glucose by using the following formula: variation of glycaemia%
¼ (AX ꢁ A0)/A0 ꢀ 100% (AX: blood glucose at selected time; A0:
initial blood glucose).
Compound 34. White solid; mp: 189–190 ꢂC; 1H NMR (400 MHz,
d6-DMSO) d 12.72 (s, 2H), 8.67 (d, J ¼ 4.9 Hz, 2H), 8.23 (dd, J ¼ 8.4,
4.8 Hz, 2H), 8.04 (dd, J ¼ 14.0, 8.7 Hz, 2H), 7.14 (d, J ¼ 8.7 Hz, 1H),
6.76 (d, J ¼ 10.5 Hz, 1H), 6.64 (s, 1H), 4.66 (s, 2H), 4.34 (s, 2H), 2.25
(d, J ¼ 12.0 Hz, 1H), 2.01 (d, J ¼ 11.6 Hz, 1H), 1.78–1.48 (m, 2H), 1.15
(s, 3H), 1.09 (s, 3H). 13 C NMR (300 MHz, d6-DMSO) d 179.9, 167.6,
166.0, 156.3, 142.6, 136.3, 134.8, 134.5, 130.9, 130.7, 130.6, 130.4,
130.3, 129.3, 126.5, 126.0, 125.8, 114.5, 113.2, 66.1, 64.4, 46.8, 45.3,
38.3, 36.7, 30.2, 25.3, 21.5, 18.6, 16.8. HRMS: m/z calcd for
C31H32O7 [M þ H]þ 517.2221, found 517.2231.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The project was sponsored by grants from the National Natural
Science Foundation for the Youth of China (81302647), Chengdu
Technology Innovation Research Project (2018-YFYF-00195-SN),
Sichuan Science and Technology Innovation Seedling Project
(2018082), Science and Technology Department of Sichuan
Province (2016HH0075), the Found of Sichuan Education
Department (18TD0023), Open Project of School of Health
Management of Xihua University (SZJJ2017-038), and the
Innovation Fund of Xihua Scholars, Undergraduate and Post
Graduate from Xihua University.
4.2. Biological assays
4.2.1. PTP1B inhibition assay
The inhibitory assay was performed using human PTP1B (pur-
chased from Sigma) and p-nitrophenylphosphate (pNPP) as sub-
strate by UV absorption. 400 nmol pNPP were dissolved in H2O
and 48 lL of the solution was added to a 100 lL reaction. The
indicated amount of synthetic compounds was diluted in DMSO
at a concentration of 5 mM. The PTP1B was diluted in pH 7.2 buf-
fer contained 50 mM HEPES, 3 mM dithiothreitol, 2 mM EDTA and
100 mM NaCl. About 50 lL PTP1B dilution was added, and the
mixture incubated at 37 ꢂC for 30 min. 1N NaOH was added to ter-
minate the reaction. UV–Vis absorption was detected at 410 nm
using a Tecan Infinite M1000 plate reader.
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