Isolation, semi-synthesis, docking-based prediction, and bioassay-based activity ofDolichandrone spathaceairidoids: new catalpol derivatives as glucosidase inhibitors

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Isolation, semi-synthesis, docking-based

prediction, and bioassay-based activity of

Dolichandrone spathacea iridoids: new catalpol

derivatives as glucosidase inhibitors†

Cite this: RSC Adv., 2021, 11, 11959

ab

c

d

e

Tran Thi Phuong Thao,‡ Thanh Q. Bui,‡ Phan Tu Quy, Nguyen Chi Bao, Tran Van

ab

bf

ab

Loc, Tran Van Chien, Nguyen Linh Chi, Nguyen Van Tuan, Tran Van Sung*

c

and Nguyen Thi Ai Nhung

*

Dolichandrone spathacea iridoids are promising anti-diabetic inhibitors towards a-glucosidase protein

PDB-3W37) and oligo-1,6-glucosidase protein (PDB-3AJ7). Five catalpol iridoids (1, 2, 10, 13, 14) were

isolated from mangrove plant D. spathacea, and their derivatives (3, 4, 5, 6, 7, 8, 9, 11, 12, 15) were

obtained from reduction, acetylation, O-alkylation, acetonisation, or hydrolysation starting from naturally

isolated compounds. They were identiﬁed by spectral methods such as IR, MS, and 1D and 2D NMR.

Their glucosidase-related (3W37 and 3AJ7) inhibitability and physiological compatibility were predicted

by molecular docking simulation and prescreened based on Lipinski's rule of ﬁve. Experimental a-

glucosidase inhibition of 1–15 was evaluated using enzyme assays. Compounds 3, 4, 5, 6, and 9 are new

iridoid derivatives, introduced to the literature for the ﬁrst time, while all ﬁfteen compounds 1–15 are

studied for molecular docking for the ﬁrst time. Regarding protein 3W37, the ﬁve strongest predicted

inhibitors assemble in the order 2 > 10 > 1 > 9 > 14. In respect to 3AJ7, the corresponding order is 14 > 2

10 > 5 > 1 ¼ 9. Lipinski's criteria suggest 10 as the candidate with the most potential for oral

administration. The in vitro bioassay revealed that compound 10 is the most eﬀective inhibitor with

a respective IC50 value of 0.05 mM, in the order 10 > 2 > 14 > 13 > 1. The computational and

experimental results show good consistency. The study opens an alternative approach for diabetes

treatment based on inhibitability of natural and semi-synthesised catalpol iridoid derivatives towards

carbohydrate-hydrolases.

(

>

Received 18th January 2021

Accepted 16th March 2021

DOI: 10.1039/d1ra00441g

rsc.li/rsc-advances

evidence suggesting a relationship between this disease and the

1

. Introduction

causes of cardiovascular diseases, blindness, kidney failure,

3

Diabetes mellitus (DM) has become prevalent in the past stroke, and limb amputation. In particular, type 2 DM is

decades, especially in the middle-income countries. According a noninsulin-dependent disorder, stemmed from the ineﬀective

to the International Diabetes Federation, it was responsible for use of insulin in the body and accounting for 90–95% of total

1

4

about 4.2 million deaths in 2019 and is predicted to be the diabetes cases.

2

seventh leading cause of death by 2030 (WHO). Also, there is

There are many kinds of medicines for the treatment of type-

2

diabetes, based on insulin sensitizers, sodium glucose

a

transporter-2 (SGLT-2) inhibitors, glucagon like peptidase-1

(GLP-1) analogues and dipeptidyl peptidase-4 (DPP-IV) inhib-

Graduate University of Science and Technology, Vietnam Academy of Science and itor mechanisms. However, these therapies have signicant

Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc

Viet Road, Cau Giay, Hanoi, Vietnam. E-mail: tranvansungvhh@gmail.com

b

Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, Vietnam

side eﬀects such as weight gain, cardiovascular risks, and

atherosclerosis as well as limited tolerability. Therefore, the

approach for type 2 DM changes into the inhibition of gluco-

sidase enzymes, which slows down of glucose absorption

c

Department of Chemistry, University of Sciences, Hue University, Hue City, Vietnam.

E-mail: ntanhung@hueuni.edu.vn

d

Department of Natural Sciences & Technology, Tay Nguyen University, Buon Ma

Thuot, Vietnam

e

through intestinal wall. There are two main types of glucosidase

responsible for carbohydrate break-down processes in the body,

regarding their sources: a-glucosidase and oligo-1,6-

Hue University, Hue City, Vietnam

f

Asean College of Medicine and Pharmacy, Trung Trac street, Van Lam district, Hung

Yen province, Vietnam

†

1

‡

Electronic supplementary information (ESI) available. See DOI: glucosidase. First, a-glucosidase is an exoenzyme found in

0.1039/d1ra00441g

5

animal, plant, bacterial, or fungal organisms, especially from

These authors contributed equally to this work.

©

2021 The Author(s). Published by the Royal Society of Chemistry

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6

sugar beet seeds. This type of glucosidase was demonstrated

only catalysing hydrolysis of a-(1/4) and a-(1/6) bonds to

7

yield monosaccharides. Protein structural data of a-glucosi-

dase can be referenced at Worldwide Protein Data Bank under

entry PDB-3W37 (DOI: 10.2210/pdb3W37/pdb). Second, oligo-

1,6-glucosidase, oen called isomaltase, is a debranching

endoenzyme, hydrolysing only the a-1,6 linkage in starch and

8

glycogen to produce sugars with an a-conguration. Unlike a-

glucosidase, they are not responsible for a-1,4 linkage hydro-

lysis. Oligo-1,6-glucosidase is mainly found in animals although

some bacterial species, such as Bacillus cereus, can also syn-

9

thesise it. In humans, it is located on the small intestine brush

10

Fig. 1 (A) a-Glucosidase protein 3W37 (DOI: 10.2210/pdb3W37/pdb)

and (B) oligo-1,6-glucosidase protein 3AJ7 (DOI: 10.2210/pdb3AJ7/

pdb) referenced from Worldwide Protein Data Bank.

border. Information for isomaltase crystal structure can be

downloaded directly from Worldwide Protein Data Bank data-

base under entry PDB-3AJ7 (DOI: 10.2210/pdb3AJ7/pdb).

Therefore, 3W37 and 3AJ7 are considered as highly promising

drug targets for eﬀective treatment of type-2 diabetes, especially

medication through oral administration. In principle, multiple

inhibition of these enzymes (3W37 and 3AJ7) is considered as

an eﬃcacious strategy to suppress the hyperglycemia and

improve insulin sensitisation, simultaneously. Crystal structure

of the proteins are shown in Fig. 1.

signicance regarding a variety of ligand families, e.g. thiazo-

17

18

19

lidinedione, pyrazole–rhodanine, or wedelolactone.

Catalpol and catalpol analogues, containing epoxy ring at C-

and C-8, are widely found in many plants belonging to some

families such as Plantaginaceae, Lamiaceae, Bignonicaceae.

7

20

Recently, there is an increasing numbers of papers reported

In silico technique, based on computational simulation and

computing calculation, is currently seeing a gain of their

popularity for medical science as prescreening research. It is for

reducing cost and time of wet laboratory experiments by pre-

dicting the compounds with undesirable properties and the

most promising candidates. The former substances are deemed

to be eliminated from the next analysis or further-developed

about the anti-diabetic eﬃcacy of catalpol derivatives in the

20,21

management of diabetes and its complications.

It has been

showed that catalpol-type iridoids are able to restore diabetic

liver function by improving glucose and lipid metabolism,

ameliorating oxidative stress, and restoring mitochondrial

function. They improve glucose uptake and lipolysis by upre-

gulating the expression of glucose transporter as well as

downregulating the expressions of peroxisome proliferators in

11

research, while the latter justies the selection. Regarding

ligand–protein interaction, molecular docking simulation is an

eﬀective method to investigate the potency of a ligand as an

inhibitor towards its targeted protein. The method can estimate

ligand-target binding energy and intermolecular interaction,

20

mice. Therefore, catalpol derivatives have become a very

promising scaﬀold for the development of anti-diabetic drug

candidates. Our previous study on chemical constituents of the

mangrove plant Dolichandrone spathacea led to the isolation of

12

thus predicting static stability of the inhibitory systems.

22

four catalpol iridoids.

This seems reasonable because

Eﬀectively inhibited by external ligands, the enzyme is likely to

undergo conformational changes, thus loss of enzymatic func-

tionality inevitably ensuing. This might help mitigating the

amount of glucose catalytically synthesised and excreted to

bloodstream. According to the methodology of molecular

docking simulation applied for ligand–protein inhibitory

systems in general and to the evaluation from.

Molecular Operating Environment (MOE)-based algorithms

in particular, an associated docking score (DS) is considered as

the main indicator for inhibitory eﬀects, of which value lower

according to folk experiences, the plant is currently reported as

a natural symptom reliever for diabetes, especially in Mekong

Delta, Vietnam. Nevertheless, its chemical properties and

medical potentiality still remain almost untouched possibly

because of their narrow distribution.

In this paper, ten derivatives from the isolated compounds

were synthesized, together with natural compounds they were

ꢀ

1

13–15

than ꢀ3.2 kcal mol indicates good binding capacity.

In

principle, the gure is yielded by the free-energy sum of all

individual intermolecular interactions, of which aﬃnity stems

from hydrophilic bonding, i.e. various hydrogen-bond types,

and hydrophobic binding, i.e. van der Waals forces. Besides,

˚

a root-mean-square deviation (RMSD) value over 3 A reveals that

the inhibition expects failure; meanwhile, the threshold of

docking success is widely acceptable if #2A^˚ .¹⁶Also, visual

illustration for inhibitory morphology and interaction descrip-

tion is oen provided. Specication to drug design for diabetes,

molecular docking technique demonstrated its contributive

Fig. 2 Structural formula of commercial medicines for diabetes

treatment (D1) acarbose, (D2) miglitol, and (D3) voglibose.

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studied in molecular docking experiment on sugar beet a-

glucosidase protein (PDB-3W37) and oligo-1,6-glucosidase

2.1.3 Synthesis of catalpol derivatives

2.1.3.1 General procedure for the synthesis of 3, 4. To a stirred

protein (PDB-3AJ7). Three commercial medicines acarbose solution of 1 or 2 (0.1 mmol) dissolved in MeOH (5 mL) was

D1), miglitol (D2), and voglibose (D3) had been reported able to added NiCl $6H O (0.5 mmol). The reaction mixture was stirred

(

2

ꢁ

lengthen the duration time of carbohydrate absorption and for 10 minutes at room temperature and cooled to 0 C. NaBH₄

atten the blood-glucose concentrations, thus widely used in (18.9 mg, 0.5 mmol) was slowly added to the mixture, which was



23

ꢁ

the treatment for patients with type 2 diabetes. Therefore, they then allowed to stir at 0 C for 30 minutes and one additional

were specied as references in this study. Their structural hour at room temperature. The reaction mixture was then

formula is presented in Fig. 2.

removed the solvent to obtain a white solid. The solid was dis-

solved in CH Cl

and the solution was washed with water (2 ꢂ

0 mL), dried over anhydrous Na SO , and evaporated the

solvent. The crude product was puried over a silica gel column

CH Cl /MeOH 9 : 1) to obtain 3 (46 mg, yield: 83%) or 4

.1.1 Material and methods. All analytically graded (44.5 mg, yield: 80.6%).

reagents were purchased from either Sigma-Aldrich or Merck &

2.1.3.2 Synthesis of 5. To a solution of 4 (55.2 mg, 0.1 mmol)

2

3

2

4

2. Methodology

2.1. Experiments

(

2

Co. and used without further purication. Solvents for column in pyridine (2 mL) was added anhydride acetic acid (2 mL). Aer

chromatography were distilled before use. Melting points (in stirring for 12 hours at room temperature, the reaction mixture

ꢁ

C) were determined on a Thermo Mel-temp 3.0 (USA). Infrared was added CH Cl (20 mL) and HCl (1 N) to pH ¼ 6, following by

2

(

IR) spectra were recorded on an IMPACT 410 Nicolet Spec- washing with a solution of NaHCO (5%) (2 ꢂ 10 mL) and water

3

trometer. ESI-MS spectra were obtained from an 1100 Agilent (2 ꢂ 10 mL). The organic layer was evaporated to obtain the

1

13

LC/MS ion Trap. 1D ( H, C and DEPT) and 2D (HSQC, HMBC, crude product which was puried by silica gel column chro-

COSY, NOESY) NMR spectra were recorded on a Bruker Avance matography (n-hexane/ethyl acetate 2 : 1) to aﬀord 5 (61.1 mg,

5

00 MHz using tetramethylsilane (TMS) as the internal standard 80%).

1

13

for H and solvent signal for C NMR. Thin-layer chromatog-

raphy (TLC) was carried out on a pre-coated silica gel 60 F254 in dried CHCl (3 mL) and pyridine (0.5 mL) was added tri-

2.1.3.3 Synthesis of 6. To a solution of 2 (55.2 mg, 0.1 mmol)

3

(Merck & Co.), visualised under ultraviolet (UV) radiation at lmax phenylmethyl chloride (55.6 mg, 0.2 mmol). The reaction

254 nm, and stained by a solution of 1% (w/w) vanillin in mixture was allowed to stir for 12 hours at room temperature.

sulfuric acid. Column chromatography (CC) was performed on The solvent was then removed under reduced pressure to give

silica gel 300–400 mesh (Merck & Co.). Enzyme a-glucosidase white solid which was dissolved in CHCl (30 mL) and washed

3

was purchased from Sigma-Aldrich under the name code with water (2 ꢂ 30 mL). The organic layer was dried over

G0660, detected by a Biotek Epoch 2 microplate readers (USA). anhydrous Na SO , evaporated the solvent to aﬀord a yellow

2

4

2

.1.2 Isolation of catalpol iridoids from Dolichandrone solid, which was puried by silica gel column chromatography

spathacea

(CH Cl /MeOH/pyridine 98 : 2 : 0.5) to obtain 6.

.1.2.1 Isolation of catalpol iridoids 1, 2, 13, 14. The proce-

dures for the isolation of 1, 2, 13 and 14 were described in ref. a solution of 1 or 2 or 13 or 14 (0.1 mmol) in pyridine (1 mL) was

2. Iridoid 1 and 14 were isolated from the leaves, while 2 and 13 added anhydride acetic acid (1 mL). The solution was stirred for

2

2.1.3.4 General procedure for the synthesis of 7, 8, 11, 12. To

2

were isolated from the barks of Dolichandrone spathacea 24 h at room temperature then ice cold water (10 mL) was added

collected in Soc Trang province, Vietnam. Their structures were and extracted with EtOAc (3 ꢂ 30 mL). The EtOAc extract was

2

4,25

identied as 6-O-[E-4-methoxycinnamoyl]catalpol (1),

6-O- combined, dried with anhydrous Na SO , evaporated the

2 4

26,27

28

[

(E)-3,4-dimethoxycinnamoyl]catalpol (2),

minecoside (13),

solvent to give yellow solid. The crude product was subjected to

a Sephadex LH-20 column (100% MeOH) to obtain the corre-

29

specioside (14).

2.1.2.2 Isolation of catalpol iridoid 10. Compound 10 was sponding acetylated catalpol iridoids.

isolated from the leaves of Dolichandrone spathacea collected in

2.1.3.5 Synthesis of 9. To a solution of 1 (52.4 mg, 0.1 mmol)

Phu Loc district, Thua Thien-Hue province, Vietnam in and TsOH (4 mg) in dried DMF was added dropwise 2,2-dime-

December 2018. The plant was identied by Dr Do Xuan Cam, thoxypropane (0.26 mg, 0.25 mmol). The reaction mixture was

ꢁ

University of Agriculture and Forestry, Hue University. The heated to 50 C for three hours, neutralized by triethylamine,

dried powder of the leaves of Dolichandrone spathacea (250 g) following by the addition of EtOAc (100 mL) and water (50 mL).

ꢁ

was extracted with EtOH 90% at 50 C (3 ꢂ 3 hours ꢂ 1 L). The The organic layer was separated, washed with water (2 ꢂ 50

EtOH extracts were combined and evaporated the solvent under mL), dried over anhydrous Na SO and evaporated the solvent

2

4

reduced pressure. The obtained residue (37 g) was suspended in to give a white solid, this was then puried by a silica gel

50 mL MeOH/H O (1 : 2) and partitioned with CH Cl . The column chromatography (DCM/MeOH 95 : 5) to obtain 9

organic layer was separated, then the remaining aqueous layer (40 mg, 71%).

3

2

was dried to obtain the residue (25 g). The residue was subjected

2.1.3.6 Synthesis of 15. Compound 2 (110.4 mg, 0.2 mmol)

to a silica gel column with a gradient of CH Cl /MeOH 100 : 0 to was dissolved in a mixture of (H O/THF/EtOH 1 : 1 : 1) and TEA

2

7

0 : 30 to give four fractions Fr.1–Fr.4. Fraction Fr.1 (2.0 g) was (1 mL). Hydroxyl amine hydrochloride (69.5 mg, 1 mmol) was

further puried by RP-18 column chromatography, eluting with then added to the solution. The reaction mixture was heated to

MeOH/H O (1 : 1) to aﬀord compound 10 (5.1 mg).

2

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ꢁ

1

00–110 C for 6 hours. The solvent was evaporated to give in format *.sdf. Docking simulation parameters were cong-

a residue which was then suspended in water and partitioned ured as: poses retaining for further inhibition analysis ¼ 10;

with EtOAc (3 ꢂ 20 mL). The organic layers were combined, maximum solutions per iteration ¼ 1000; maximum solutions

dried over anhydrous Na SO and evaporated the solvent to per fragmentation ¼ 200.

2

4

aﬀord a white solid, this was subjected to a silica gel column

2.2.1.3 Post-docking analysis. The inhibitability of a certain

chromatography (CH

0%).

2

Cl

2

/MeOH 9 : 1) to obtain 15 (65.2 mg, duo-system was primarily predicted by docking score (DS)

energy, which represents binding aﬃnity of ligands and their

9

2.1.4 Enzyme assay of a-glucosidase. Each assay was per- targeted proteins in the site–site distance. Intermolecular

formed on 96 well-plates (200 mL per well). The test samples interactions formed between the ligands and in-pose amino

were dissolved in DMSO 10% and further diluted to the acids of the proteins were also probed. These include hydro-

ꢀ1

concentrations: 1024, 256, 64, 16, 4, 1 mg.mL . Each concen- philic binding and hydrophobic interaction. The former is

ꢁ

tration of the test sample (10 mL) was incubated at 37 C with a variety of hydrogen-bond types, e.g. electron-transferring (H-

phosphate buﬀer 100 mM (pH 6.8, 40 mL), a-glucosidase 0.4 U acceptor/donor), cation–arene (H–p), arene–arene (p–p), and

ꢀ1

mL (25 mL), p-nitrophenyl a-D-glucopyranoside 2.5 mM (25 ionic; while, van der Waals forces constitute the latter. The

mL). Aer 30 minutes, the reaction was terminated by adding results provide in-bonding amino acids, bonding lengths, and

2 3

100 mL of 0.1 M Na CO solution. The enzyme activities were their Gibbs free energy. Besides, binding stability of the

determined by measuring the absorbance at lmax 410 nm. The complex static conformation was evaluated by the respective

control was prepared using the same procedure replacing the values of root-mean-square deviation (RMSD) calculated. This is

test sample by distilled water, while activity of the reference was based on the fact that RMSD represent the average between

30

tested by replacing the test sample with acarbose Percentage neighbouring atoms; therefore, a smaller value means a more

3

1

of inhibition was calculated as followed:

tightly bound conformation is formed. In addition, ligand

conformation and orientation in its inhibited-protein active site

was visualised on 2D and 3D planes.

Abscontrol ꢀ Abssample

a-glucosidase inhibition ð%Þ ¼

ꢂ 100%

Abscontrol

2

.2.2 Physicochemical and pharmaceutical compatibility.

ꢀ

1

The docking parameters including DSaverage (kcal mol ),

3

˚

molecular mass (Da), polarizability (A ) and volume or size (A),

and dispersion coeﬃcients (log P and log S) were achieved by

Gasteiger–Marsili method using QSARIS system. They were

2.2. Computation

33

2

.2.1 Molecular docking simulation. The simulation was then prescreened in an attempt to evaluate their orally phar-

carried out on MOE 2015.10 soware. The structural informa- macological compatibility. This was based on Lipinski's rule of

34

tion of targeted proteins (3W37 and 3AJ7) and docked ligands ve, a well-known set of indicators to predict drug-likeness.

iridoid compounds and referenced drugs) were required as the According to Lipinski's criteria, a well membrane-permeable

(

precursors. As conducted, this served as inputs to simulate molecule should satisfy the requirements: (1) molecular mass

intermolecular interaction between the agents, thereby yielding < 500 Da; (2) no more than 5 groups for hydrogen bonds; (3) no

information on the respective ligand-protein inhibitory more than 10 groups receiving hydrogen bonds; (4) the value of

35,36

complex. The output included inhibitory congurations, dock- log P is less than +5 (log P < 5).

ing score (DS) energy, root-mean-square deviation (RMSD),

interaction types, and distances between ligands and proteins.

3

. Results and discussion

In a typical procedure, a molecular docking simulation follows

13–15,32

3.1. Characterisation

three steps.

.2.1.1 Pre-docking preparation. Structural data of

2

3.1.1 Compound 1: 6-O-[(E)-4-methoxycinnamoyl]catalpol.

carbohydrate-hydrolase proteins 3W37 (DOI: 10.2210/ White amorphous powder, C25

H

30

O

12, ESI-MS (m/z): 523.1 [M +

+

ꢀ

ꢀ1

pdb3W37/pdb) and 3AJ7 (DOI: 10.2210/pdb3AJ7/pdb) were H] , 521.0 [M ꢀ H] ; IR (KBr, nmax, cm ): 2936 (–CH alkane),

downloaded from Worldwide Protein Data Bank. The proteins 1716 (C]O ester), 1633 (C]C alkene), 1602 (C]C–Ar), 1063 (C–

1

and their 3D protonation were prepared by MOE QuickPrep O ether); H-NMR (CD

3

OD + CDCl

3

, 500 MHz), d

H

(ppm), J (Hz):

0

00

functionality. Determination of protein active zones based upon 7.69 (1H, d, J ¼ 16.0, H-7 ), 7.55 (2H, d, J ¼ 8.0, H-2 , H-6 ), 6.95

˚

00

a radius set at 4.5 A from their amino acids and the inhibitory (2H, d, J ¼ 8.0, H-3 , H-5 ), 6.41 (1H, d, J ¼ 16.0, H-8 ), 6.36 (1H,

ligands. The preparatory protein structures obtained were saved dd, J ¼ 6.0, 1.5, H-3), 5.15 (1H, d, J ¼ 9.0, H-1), 5.05 (1H, dd, J ¼

in format *.pdb, ready for docking simulation. Independently, 7.5, 1.0, H-6), 5.00 (1H, dd, J ¼ 6.0, 1.5, H-4), 4.81 (1H, d, J ¼ 8.0,

0

the ligands, including iridoid compounds and referenced H-1 ), 4.16 (1H, d, J ¼ 13.0, H-10), 3.94 (1H, dd, J ¼ 12.0, 2.0, H-

0

00

drugs, were structurally optimised by Conj Grad for energy 6 ), 3.87 (1H, d, J ¼ 13.0, H-10), 3.84 (3H, s, 4 -OCH

3

), 3.73 (1H,

0

minimisation. The optimisation conguration was set: termi- br s, H-7), 3.68 (1H, dd, J ¼ 12.0, 2.0, H-6 ), 3.46–3.42 (1H, m, H-

ꢀ

1

0

nation for energy change ¼ 0.0001 kcal mol ; max interactions 3 ), 3.35–3.34 (1H, m, H-5 ), 3.33–3.32 (1H, m, H-2 ), 3.30–3.28

0

¼

1000; charge modication by Gasteiger–Huckel method.

(1H, m, H-4 ), 2.67–2.64 (1H, m, H-9), 2.63–2.61 (1H, m, H-5);

1

3

00

2.2.1.2 Docking investigation. Simulation on intermolecular

C-NMR (CD OD + CDCl , 125 MHz), d (ppm): 168.61 (C-9 ),

interaction between the investigated agents was performed on 162.98 (C-4 ), 146.69 (C-7 ), 142.17 (C-3), 130.98 (C-6 ), 130.90

MOE 2015.10 and the obtained inhibitory structures were saved (C-2 ), 127.92 (C-1 ), 115.31 (C-8 ), 115.26 (C-3 , C-5 ), 102.74

3

00

C

0

00

0

00

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0

(

3

1

C-4), 99.47 (C-1 ), 94.88 (C-1), 81.09 (C-6), 78.25 (C-5 ), 77.38 (C- 74.84 (C-2 ), 71.78 (C-4 ), 66.78 (C-8), 62.93 (C-10), 61.24 (C-6 ),

0

0 0 0 00 00

), 74.50 (C-2 ), 71.39 (C-4 ), 66.67 (C-8), 62.63 (C-6 ), 61.12 (C- 60.07 (C-7), 56.61 (4 -OCH ), 56.49 (3 -OCH ), 43.14 (C-9), 36.96

3 3

0), 60.05 (C-7), 55.81 (4 -OCH ), 42.89 (C-9), 36.46 (C-5).

.1.2 Compound 2: 6-O-[(E)-3,4-dimethoxycinnamoyl]cata-

lpol. White amorphous powder, C26

88.2 [M + Cl] ; IR (KBr, nmax, cm ): 2903 (–CH alkane), 1717 HR-ESI-MS (m/z): 787.2389 [M

0

00

(C-8 ), 36.62 (C-5), 31.60 (C-7 ).

3.1.5 Compound 5: 6-O-(3,4-dimethoxyphenylpropanoyl)

44 18

13, (+)-ESI-MS (m/z): catalpolpentaacetate. White amorphous powder, C36H O ,

3

H

32

O

ꢀ

ꢀ1

+

5

(

+ Na] (calculated for

+

1

C]O ester), 1635 (C]C alkene), 1594 (C]C–Ar), 1086 (C–O 18Na 787.2425), ESI-MS (m/z): 765.0 [M + H] ; H-NMR

ether); H-NMR (CD

36 44

C H O

1

3

OD + CDCl

3

, 500 MHz), d

H

(ppm), J (Hz): (CD

3

OD, 500 MHz), d

H

(ppm), J (Hz): 6.88 (2H, d, J ¼ 7.5, H-

0

00

7

(

.68 (1H, d, J ¼ 15.5, H-7 ), 7.14 (1H, dd, J ¼ 8.5, 1.5, H-6 ), 7.09 2 , H-6 ), 6.78 (1H, dd, J ¼ 7.5, 2.0, H-5 ), 6.34 (1H, dd, J ¼ 6.0,

00

1H, d, J ¼ 1.5, H-2 ), 6.90 (1H, d, J ¼ 8.5, H-5 ), 6.38 (1H, d, J ¼ 1.5, H-3), 5.30 (1H, t, J ¼ 9.5, H-6), 5.11–5.03 (3H, m, H-1, H-4, H-

00

0

1

(

5.5, H-8 ), 6.34 (1H, dd, J ¼ 4.5, 2.0, H-3), 5.05–5.00 (3H, m, H- 5 ), 4.93–4.87 (3H, m, H-2 , H-3 , H-4 ), 4.36 (1H, dd, J ¼ 12.0, 2.5,

0

, H-4, H-6), 4.84 (1H, d, J ¼ 8.0, H-1 ), 4.03 (1H, d, J ¼ 13.0, H- H-6 ), 4.23 (1H, dd, J ¼ 12.5, 4.0, H-10), 3.90 (1H, m, H-6 ), 3.84

0

00

0), 3.95 (1H, m, H-10), 3.92 (6H, s, 3 -OCH

3

, 4 -OCH

3

), 3.88 (3H, s, OCH

3

), 3.81 (3H, s, OCH

3

), 3.80 (1H, d, J ¼ 12.5 Hz, H-10),

0

00

1H, dd, J ¼ 12.0, 5.5, H-6 ), 3.78 (1H, dd, J ¼ 12.0, 5.5, H-6 ), 3.74 3.63 (1H, d, J ¼ 1.0, H-7), 2.93 (2H, t, J ¼ 7.0, H-7 ), 2.72 (2H, t, J

0

00

1H, br s, H-7), 3.52–3.48 (2H, m, H-3 , H-5 ), 3.39–3.36 (2H, m, ¼ 7.0, H-8 ), 2.56–2.52 (1H, m, H-9), 2.45–2.41 (1H, m, H-5),

0

13

0

13

H-2 , H-4 ), 2.71–2.66 (1H, m, H-9), 2.65–2.64 (1H, m, H-5); C- 10,2 ,3 ,4 ,6 -OCOCH

3

: 2.13, 2.10, 2.04, 2.03, 2.00. C-NMR

0

00

NMR (CD

1

(

1

7

6

4

3

OD + CDCl

3

, 125 MHz), d

C

(ppm): 167.32 (C-9 ), (CD

3

OD, 125 MHz), d

C

(ppm): 174.42 (C-9 ), 172.64, 172.45,

00

51.30 (C-4 ), 149.10 (C-3 ), 145.90 (C-7 ), 141.05 (C-3), 127.01 171.60, 171.14, 170.92 (5ꢂ-OCOCH ), 150.49 (C-4 ), 149.10 (C-

3

00

C-1 ), 122.86 (C-6 ), 114.64 (C-8 ), 111.00 (C-2 ), 109.72 (C-5 ), 3 ), 142.29 (C-3), 134.68 (C-1 ), 121.70 (C-6 ), 113.61 (C-2 ),

0

02.06 (C-4), 98.58 (C-1 ), 94.26 (C-1), 79.65 (C-6), 76.41 (C5 ), 113.35 (C-5 ), 102.96 (C-4), 98.09 (C-1 ), 95.92 (C-1), 81.01 (C-6),

5.97 (C-3 ), 73.02 (C-2 ), 69.29 (C-4 ), 65.42 (C-8), 60.91 (C-6 ), 74.04 (C-5 ), 73.33 (C-3 ), 72.22 (C-2 ), 69.61 (C-4 ), 64.68 (C-10),

0.53 (C-10), 59.12 (C-7), 55.81 (3 -OCH

1.76 (C-9), 35.17 (C-5).

0

00

0

00

3

), 55.76 (4 -OCH

3

), 63.65 (C-8), 62.28 (C-6 ), 59.93 (C-7), 56.61 (4 -OCH

3

), 56.49

0

00

(3 -OCH

3

), 42.72 (C-9), 36.88 (C-8 ), 36.44 (C-5), 31.56 (C-7 ),

3

.1.3 Compound 3: 6-O-(4-methoxyphenylpropanoyl)cata- 20.75, 20.71, 20.57, 20.54, 20.51 (5ꢂ-OCOCH

3

).

0

lpol. White amorphous powder, C25

47.1779 [M + Na] (calculated for C H O Na 547.1791), ESI- O-ditriphenylmethyl. White amorphous powder, C H O ,

25 32 12

MS (m/z): 559.0 [M + Cl] ; H-NMR (CD OD, 500 MHz), d

H

32

O12, HR-ESI-MS (m/z):

3.1.6 Compound 6: 6-O-[(E)-3,4-dimethoxy]catalpol-10,6 -

+

5

64 60 13

+

ꢀ

1

HR-ESI-MS (m/z): 817.2788 (100) [C H O Na] [M ꢀ C H

+

3

H

45 46 13

19 15

0

00

+

1

(

ppm), J (Hz): 7.15 (2H, d, J ¼ 8.5, H-2 , H-6 ), 6.85 (2H, d, J ¼ Na + H] (calculated for C H O Na: 817.2830); H-NMR

4

5

46 13

00

8

9

6

3

.5, H-3 , H-5 ), 6.34 (1H, dd, J ¼ 6.0, 1.5, H-3), 5.12 (1H, d, J ¼ (CDCl

3

, 500 MHz), d

H

(ppm), J (Hz): 7.69 (1H, d, J ¼ 15.5, H-

0

.5, H-1), 4.92 (1H, dd, J ¼ 8.0, 1.5, H-4), 4.79 (1H, d, J ¼ 7.5, H- 7 ), 7.39–7.15 (30H, m, 2ꢂ-OC(C

6

H

5

)

3

), 7.13 (1H, dd, J ¼ 8.0, 2.0,

0

00

), 4.15 (1H, d, J ¼ 13.0, H-10), 3.94 (1H, dd, J ¼ 12.0, 2.0, H-6 ), H-6 ), 7.07 (1H, d, J ¼ 2.0, H-2 ), 6.88 (1H, d, J ¼ 8.0, H-5 ), 6.38

0

00

.82 (1H, d, J ¼ 13.0, H-10), 3.77 (3H, s, 4 -OCH

3

), 3.65 (1H, dd, J (1H, d, J ¼ 15.5, H-8 ), 6.31 (1H, d, J ¼ 6.5, H-3), 5.01 (1H, dd, J ¼

0

¼

12.0, 6.5, H-6 ), 3.61 (1H, s, H-7), 3.41 (1H, t, J ¼ 9.0, H-3 ), 6.0, 4.0, H-1), 4.96 (1H, d, J ¼ 6.5, H-4), 4.74 (1H, d, J ¼ 9.0, H-1 ),

0

00

00 00

3

2

.35–3.26 (3H, m, H-2 , H-4 , H-5 ), 2.91 (2H, t, J ¼ 7.5, H-7 ), 4.59 (1H, d, J ¼ 8.0, H-6), 3.91 (6H, s, 3 ,4 -OCH ), 3.86 (1H, m,

3

0

.69 (2H, t, J ¼ 7.5, H-8 ), 2.60–2.57 (1H, m, H-9), 2.48–2.44 (1H, H-10), 3.75 (1H, d, J ¼ 11.5, H-10), 3.45 (1H, t, J ¼ 9.0, H-7), 3.36

1

3

00

0

m, H-5); C-NMR (CD OD, 125 MHz), d (ppm): 174.52 (C-9 ), (4H, m, H-2 , H-3 , H-4 , H-5 ), 3.27 (1H, t, J ¼ 8.5, H-6 ), 3.11 (1H,

3

C

00

0

13

1

(

8

(

59.70 (C-4 ), 142.25 (C-3), 133.69 (C-1 ), 130.34 (C-2 , C-6 ), m, H-6 ), 2.76 (1H, t, J ¼ 8.5, H-9), 2.68 (1H, d, J ¼ 8.5, H-5); C-

0

00

0

00

14.93 (C-3 , C-5 ), 102.85 (C-4), 99.70 (C-1 ), 95.04 (C-1), 81.32 NMR (CDCl

3

00

, 125 MHz), d

C

(ppm): 166.98 (C-9 ), 151.43 (C-4 ),

), 128.80–127.25 (2ꢂ-

0

C-6), 78.62 (C-5 ), 77.70 (C-3 ), 74.83 (C-2 ), 71.77 (C-4 ), 66.77 (C- 149.34 (C-3 ), 146.92 (2ꢂ-OC(C

6 5 3

H )

0

00

0 00

), 62.92 (C-10), 61.24 (C-6 ), 60.07 (C-7), 55.68 (4 -OCH

3

), 43.13 OC(C

141.09 (C-3), 127.09 (C-1 ), 122.83 (C-6 ), 115.15 (C-8 ), 111.18

6 5 3

H ) ), 87.48 and 86.60 (C-10 and C-6 ), 145.68 (C-7 ),

0

00

C-9), 37.04 (C-8 ), 36.60 (C-5), 31.15 (C-7 ).

3

catalpol. White amorphous powder, C H O , HR-ESI-MS (m/ (C-6), 76.80 (C-5 ), 76.30 (C-3 ), 73.57 (C-2 ), 72.54 (C-4 ), 65.09 (C-

z): 577.1867 [M + Na] (calculated for C H O Na 577.1897), 8), 64.48 (C-6 ), 61.22 (C-10), 59.04 (C-7), 55.93 (3 ,4 -OCH ),

0

00

0

.1.4 Compound 4: 6-O-(3,4-dimethoxyphenylpropanoyl) (C-2 ), 109.82 (C-5 ), 102.44 (C-4), 97.27 (C-1 ), 93.72 (C-1), 79.65

0

2

6

34 13

+

0

00 00

2

6

34 13

3

ꢀ

1

ESI-MS (m/z): 589.1 [M + Cl] ; H-NMR (CD

3

00

OD, 500 MHz), d

H

42.80 (C-9), 35.53 (C-5).

3.1.7 Compound 7: minecoside pentaacetate. White

19, HR-ESI-MS (m/z): 813.2209 [M +

0

(

8

ppm), J (Hz): 6.88 (2H, d, J ¼ 8.0, H-2 , H-6 ), 6.80 (1H, dd, J ¼

0

.0, 2.0, H-5 ), 6.34 (1H, dd, J ¼ 6.0, 2.0, H-3), 5.12 (1H, d, J ¼ 9.5, amorphous powder, C37

H

42

O

+

H-1), 4.92 (1H, dd, J ¼ 7.0, 1.5, H-4), 4.79 (1H, d, J ¼ 8.0, H-6), Na] (calculated for C37

H

42

O

19Na 813.2218), 791.2336 [M + H]

0

1

4

3

9

.15 (1H, d, J ¼ 13.0, H-10), 3.94 (1H, dd, J ¼ 12.0, 2.0, H-6 ), (calculated for C37

43 3

H O19 791.2399); H-NMR (CDCl , 500 MHz),

0

.84–3.82 (1H, m, H-10), 3.83 (3H, s, OCH ), 3.81 (3H, s, OCH ),

d

H

(ppm), J (Hz): 7.63 (1H, d, J ¼ 16.0, H-7 ), 7.08–7.07 (3H, m,

3

0

00

.65 (1H, dd, J ¼ 12.0, 6.5, H-6 ), 3.61 (1H, s, H-7), 3.41 (1H, t, J ¼ H-2 , H-3 , H-6 ), 7.00 (1H, d, J ¼ 8.0, H-5 ), 6.38 (1H, d, J ¼ 16.0,

0

00

.0, H-3 ), 3.33–3.25 (3H, m, H-2 , H-4 , H-5 ), 2.93 (2H, t, J ¼ 7.5, H-8 ), 6.27 (1H, dd, J ¼ 6.0, 1.5, H-3), 5.18–5.15 (1H, m, H-1),

00

0

H-7 ), 2.72 (2H, t, J ¼ 7.5, H-8 ), 2.60–2.57 (1H, m, H-9), 2.48– 5.09–5.05 (1H, m, H-6), 4.96–4.90 (4H, m, H-4, H-2 , H-3 , H-

1

3

0

2

1

(

.43 (1H, m, H-5); C-NMR (CD

3

OD, 125 MHz), d

C

(ppm): 4 ), 4.82–4.79 (2H, m, H-1 , H-5 ), 4.26 (1H, dd, J ¼ 12.0, 2.0, H-

00

0

74.55 (C-9 ), 150.47 (C-4 ), 149.07 (C-3 ), 142.28 (C-3), 134.74 6 ), 4.13 (1H, dd, J ¼ 12.0, 4.0, H-6 ), 3.92 (1H, d, J ¼ 12.5, H-10),

0

00

C-1 ), 121.70 (C-6 ), 113.59 (C-2 ), 113.33 (C-5 ), 102.82 (C-4), 3.80 (3H, s, 4 -OCH

3

), 3.69 (1H, overlap, H-10), 3.66 (1H, br s, H-

0

9

9.70 (C-1 ), 95.04 (C-1), 81.36 (C-6), 78.64 (C-5 ), 77.71 (C-3 ), 7), 2.61–2.58 (1H, m, H-9), 2.57–2.54 (1H, m, H-5), 2.25 (3H, s),

©

2021 The Author(s). Published by the Royal Society of Chemistry

RSC Adv., 2021, 11, 11959–11975 | 11963

View Article Online

RSC Advances

Paper

0

13

00

2

.06 (6H, s), 1.98 (3H, s), 1.97 (3H, s), 1.95 (3H, s) (5ꢂ-OCOCH

3

); H-10 ); C-NMR (CD

3

OD, 125 MHz), d

C

00

(ppm): 169.34 (C-1 ),

1

3

00

C-NMR (CDCl , 125 MHz), d (ppm): 170.96, 170.87, 170.37, 144.15 (C-3 ), 142.38 (C-3), 138.37 (C-6 ), 128.60 (C-2 ), 125.74

3

C

0

00

0

1

4

1

69.51, 169.32, 168.97 (5ꢂ-OCOCH ), 166.72 (C-9 ), 151.32 (C- (C-7 ), 102.91 (C-4), 99.72 (C-1 ), 95.08 (C-1), 81.62 (C-6), 78.65

3

0

00

0

), 245.26 (C-7 ), 141.57 (C-3 ), 141.03 (C-3), 132.97 (C-1 ), (C-3 ), 77.72 (C-2 ), 74.85 (C-5 ), 71.78 (C-4 ), 66.79 (C-8), 62.93 (C-

00

0

00

23.18 (C-6 ), 121.32 (C-8 ), 117.20 (C-2 ), 111.30 (C-5 ), 101.89 10), 61.27 (C-6 ), 60.17 (C-7), 59.37 (C-8 ), 43.17 (C-9), 39.06 (C-

0 0 00 00 00 00

(

3

C-4), 96.50 (C-1 ), 94.16 (C-1), 79.50 (C-6), 72.50 (C-5 ), 72.12 (C- 5 ), 36.67 (C-5), 28.06 (C-4 ), 16.18 (C-10 ), 12.47 (C-9 ).

0

00

), 68.12 (C-4 ), 62.58 (C-8), 62.32 (C-6 ), 58.77 (C-7), 55.80 (4 -

), 41.47 (C-9), 34.96 (C-5), 20.51 (–OCOCH ), 20.46 lpolhexaacetate. White amorphous powder, C35

–OCOCH ).

), 20.43 (3ꢂ-OCOCH

.1.8 Compound 8: 6-O-[(E)-3,4-dimethoxycinnamoyl]cata- NMR (CD OD, 500 MHz), d (ppm), J (Hz): 7.70 (1H, d, J ¼

3.1.11 Compound 11: 6-O-[(E)-4-methoxycinnamoyl]cata-

OCH

(

3

40

H O

17, ESI-MS

+

+ 1

3

2 2

(m/z): 755.0 [M + Na + H O] , 791.1 [M + Na + 2H O] ; H-

3

H

0

00

lpolpentaacetate. White amorphous powder, C H O , (+)-ESI- 15.5, H-7 ), 7.49 (2H, d, J ¼ 8.5, H-2 , H-6 ), 6.91 (2H, d, J ¼ 8.5,

3

6

42 18

+

1

00

MS (m/z): 763.9 [M + H] ; H-NMR (CD OD, 500 MHz), d (ppm), H-3 , H-5 ), 6.35 (1H, d, J ¼ 15.5, H-8 ), 6.31 (1H, d, J ¼ 6.0, H-3),

3

H

0

J (Hz): 7.68 (1H, d, J ¼ 16.0, H-7 ), 7.12 (1H, dd, J ¼ 8.0, 1.5, H- 5.25–5.23 (1H, m, H-1), 5.16–5.12 (1H, m, H-6), 5.02–4.97 (1H,

0

00

0

6

), 7.07 (1H, d, J ¼ 1.5, H-2 ), 6.87 (1H, d, J ¼ 8.0, H-5 ), 6.36 m, H-4), 4.98–4.96 (3H, m, H-2 , H-3 , H-4 ), 4.89–4.86 (2H, m, H-

00

0

(

1H, d, J ¼ 16.0, H-8 ), 6.32 (1H, dd, J ¼ 6.0, 1.5, H-3), 5.25–5.21 1 , H-5 ), 4.30 (1H, dd, J ¼ 12.0, 2.0, H-6 ), 4.21 (1H, dd, J ¼ 12.0,

0

00

(

1H, m, H-1), 5.16–5.12 (1H, m, H-6), 5.03–4.96 (4H, m, H-4, H- 4.0, H-6 ), 3.99 (1H, d, J ¼ 12.5, H-10), 3.83 (3H, s, 4 -OCH

3

), 3.73

0

2

1

3

5

1

, H-3 , H-4 ), 4.89–4.85 (2H, m, H-1 , H-5 ), 4.31 (1H, dd, J ¼ (1H, overlap, H-10), 3.71 (1H, br s, H-7), 2.69–2.66 (1H, m, H-5),

0

2.5, 2.5, H-6 ), 4.21 (1H, dd, J ¼ 12.5, 4.0, H-10), 3.99 (1H, d, J ¼ 2.64–2.62 (1H, m, H-9), 2.13 (3H, s), 2.12 (3H, s), 2.05 (3H, s),

0

00

0

13

2.5, H-10), 3.91 (6H, s, 3 -OCH , 4 -OCH ), 3.73 (1H, m, H-6 ), 2.05 (3H, s), 2.04 (3H, s), 2.01 (3H, s) (6ꢂ-OCOCH ); C-NMR

3

.71 (1H, br s, H-7), 2.70–2.65 (1H, m, H-9), 2.64–2.62 (1H, m, H- (CDCl , 125 MHz), d (ppm): 170.62 (2ꢂ-OCOCH ), 170.46

3

C

3

1

3

); C-NMR (CDCl

3

, 125 MHz), d

C

(ppm): 170.70, 170.54, 170.22, (–OCOCH

3

), 170.16 (–OCOCH

3

), 169.23 (–OCOCH

3

00

), 169.02

0

00

69.28, 169.07 (5ꢂOCOCH

3

), 167.05 (C-9 ), 151.39 (C-4 ), 149.21 (–OCOCH

3

), 167.12 (C-9 ), 161.64 (C-4 ), 145.63 (C-7 ), 141.01

00 00 00 00 00 00 00 00

(

C-3 ), 145.92 (C-7 ), 141.06 (C-3), 127.07 (C-1 ), 122.91 (C-6 ), (C-3), 129.88 (C-2 , C-6 ), 126.85 (C-1 ), 114.54 (C-8 ), 114.38 (C-

00 00 00 00 00 0

14.72 (C-8 ), 111.01 (C-2 ), 109.59 (C-5 ), 102.09 (C-4), 96.57 (C- 3 , C-5 ), 102.13 (C-4), 96.59 (C-1 ), 94.26 (C-1), 79.26 (C-6), 72.53

1

6

0

), 94.23 (C-1), 79.28 (C-6), 72.51 (C-5 ), 72.26 (C-3 ), 68.15 (C-4 ), (C-5 ), 72.28 (C-3 ), 70.57 (C-2 ), 68.20 (C-4 ), 62.53 (C-8), 62.32 (C-

2.57 (C-8), 62.35 (C-6 ), 61.16 (C-10), 58.85 (C-7), 55.95 (3 - 6 ), 61.19 (C-10), 58.83 (C-7), 55.34 (4 -OCH ), 41.55 (C-9), 34.99

OCH₃), 55.85 (4 -OCH ), 41.53 (C-9), 35.01 (C-5), 20.70 (C-5), 20.66 (–OCOCH ), 20.61 (–OCOCH ), 20.58 (–OCOCH ),

0

00

0

00

3

00

3

(

–OCOCH ), 20.65 (–OCOCH ), 20.61 (–OCOCH ), 20.57 (2ꢂ- 20.54 (3ꢂ-OCOCH ).

3

OCOCH

3

).

3.1.12 Compound 12: specioside hexaacetate. White

18; (+)-ESI-MS (m/z): 783.2 [M +

, 500 MHz), d (ppm), J (Hz): 7.77 (1H, d, J

3

40

.1.9 Compound 9: 6-O-[(E)-4-methoxycinnamoyl]catalpol- amorphous powder, C36H O

0

+ 1

4

,6 -acetonide. White amorphous powder, C28

H

34

O

12, HR-ESI- Na] ; H-NMR (CDCl

3

H

+

00

MS (m/z): 585.1956 [M + Na] (calculated for C28

5

H

34

O

12Na ¼ 16.0, H-7 ), 7.70 (2H, d, J ¼ 8.5, H-2 , H-6 ), 7.19 (2H, d, J ¼

1

00

85.1948); H-NMR (CDCl

3

, 500 MHz), d

H

(ppm), J (Hz): 7.68 8.5, H-3 , H-5 ), 6.60 (1H, d, J ¼ 16.0, H-8 ), 6.40 (1H, d, J ¼ 5.5,

00

(

1H, d, J ¼ 15.5, H-7 ), 7.39 (2H, dd, J ¼ 7.0, 2.0, H-2 , H-6 ), 6.91 H-3), 5.31 (1H, t, J ¼ 9.5, H-1), 5.13–5.12 (1H, m, H-6), 5.09–5.02

0

00

0

2H, dd, J ¼ 7.0, 2.0, H-3 , H-5 ), 6.37 (1H, m, H-8 ), 6.35 (1H, m, (4H, m, H-4, H-2 , H-3 , H-4 ), 5.00–4.98 (1H, m, H-5 ), 4.94 (1H,

0

H-3), 5.04 (1H, m, H-1), 5.02 (1H, m, H-6), 4.93 (1H, m, H-4), 4.89 m, H-1 ), 4.38 (1H, dd, J ¼ 12.5, 2.5, H-6 ), 4.23 (1H, dd, J ¼ 12.5,

0

(

5

1H, m, H-1 ), 4.03 (1H, d, J ¼ 10.5, H-6 ), 3.97 (1H, dd, J ¼ 11.0, 4.0, H-6 ), 3.93 (1H, overlap, H-10), 3.81 (1H, d, J ¼ 12.5, H-10),

0

.5, H-4 ), 3.76 (1H, d, J ¼ 10.5, H-6 ), 3.53 (1H, m, H-3 ), 3.38 3.76 (1H, br s, H-7), 2.61–2.60 (2H, m, H-5, H-9), 2.30 (3H, s),

0

(

2H, m, H-2 , H-5 ), 2.73 (1H, dd, J ¼ 10.0, 8.0, H-9), 2.66 (1H, m, 2.14 (3H, s), 2.12 (3H, s), 2.04 (6H, s), 2.00 (3H, s) (6ꢂ-OCOCH

3

);

0

13

H-5), 1.53 and 1.45 (each 3H, s, 7 -CH

3

); C-NMR (CDCl

3

, 125

C-NMR (CDCl

3

, 125 MHz), d

C

(ppm): 172.68, 172.49, 171.62,

0

00

MHz), d

1

C

(ppm): 167.21 (C-9 ), 161.69 (C-4 ), 145.66 (C-7 ), 171.16, 170.95, 170.77 (6ꢂOCOCH

3

), 168.13 (C-9 ), 154.03 (C-

00 00 00 00 00 00 00 00 00

41.06 (C-3), 129.95 (C-2 , C-6 ), 125.96 (C-1 ), 114.67 (C-8 ), 4 ), 146.03 (C-7 ), 142.43 (C-3), 133.31 (C-1 ), 130.56 (C-2 , C-6 ),

00

0

00

0

14.44 (C-3 , C-5 ), 102.51 (C-4), 99.97 (C-7 ), 99.43 (C-1 ), 94.84 123.45 (C-3 , C-5 ), 118.39 (C-8 ), 103.02 (C-4), 98.13 (C-1 ),

0

(C-1), 79.46 (C-6), 74.25 (C-5 ), 73.54 (C-3 ), 72.92 (C-2 ), 67.89 (C- 95.98 (C-1), 81.26 (C-6), 74.05 (C-5 ), 73.36 (C-3 ), 72.23 (C-2 ),

0

00

0

4

), 65.20 (C-8), 61.92 (C-6 ), 61.42 (C-10), 59.19 (C-7), 55.40 (4 - 69.63 (C-4 ), 64.76 (C-8), 63.73 (C-6 ), 60.06 (C-7), 42.79 (C-9),

0

OCH

3

), 42.10 (C-9), 36.50 (C-5), 29.00 and 20.70 (7 -CH

.1.10 Compound 10: nemoroside. White amorphous OCOCH

3

).

36.59 (C-5), 20.90, 20.77, 20.73, 20.59, 20.54, 20.52 (6ꢂ

).

3.1.13 Compound 13: minecoside. White amorphous

3

+

powder, C25

MS (m/z): 563.0 [M + Cl] ; H-NMR (CD

(

6

H

36

O

12; (+)-ESI-MS (m/z): 551.1 [M + Na] , (ꢀ)-ESI-

ꢀ 1

1

3

OD, 500 MHz), d

H

powder, C25

H

30

O

13; H-NMR (CD

3

OD, 500 MHz), d

H

(ppm), J

0

00

ppm), J (Hz): 6.74 (1H, dd, J ¼ 7.0, 6.5, H-3 ), 6.26 (1H, dd, J ¼ (Hz): 7.68 (1H, d, J ¼ 16.0, H-7 ), 7.21 (1H, br s, H-2 ), 7.11 (1H,

0

00

.0, 1.5, H-3), 5.30 (1H, m, H-7 ), 5.06 (1H, d, J ¼ 9.5, H-1), 4.85 dd, J ¼ 8.0, 1.5, H-6 ), 6.82 (1H, d, J ¼ 8.0, H-5 ), 6.40–6.38 (1H,

0

00

(

2H, m, H-4, H-6), 4.70 (1H, overlap, H-1 ), 4.05 (1H, d, J ¼ 13.0, m, H-3), 6.39 (1H, overlap, H-8 ), 5.18 (1H, d, J ¼ 9.5, H-1), 5.05

0

H-10), 3.99 (2H, d, J ¼ 6.5, H-8 ), 3.83 (1H, dd, J ¼ 12.0, 1.5, H- (1H, d, J ¼ 7.0, H-6), 5.00 (1H, dd, J ¼ 6.0, 4.0, H-4), 4.78 (1H, d, J

0

6

), 3.72 (1H, d, J ¼ 13.0, H-10), 3.57 (1H, s, H-7), 3.54 (1H, dd, J ¼ 8.0, H-1 ), 4.18 (1H, d, J ¼ 13.0, H-10), 3.95 (1H, dd, J ¼ 12.0,

0

00

¼

12.0, 6.5, H-6 ), 3.30 (1H, t, J ¼ 9.0, H-2 ), 3.21 (1H, m, H-3 ), 2.5, H-6 ), 3.92 (3H, s, 4 -OCH

3

), 3.88 (1H, d, J ¼ 13.0, H-10), 3.72

0

3

.16–3.14 (1H, m, H-4 , H-5 ), 2.52–2.46 (2H, m, H-5, H-9), 2.26 (1H, br s, H-7), 3.67 (1H, dd, J ¼ 12.0, 6.5, H-6 ), 3.45–3.41 (1H,

00 00 00 0 0 0 0

(

2H, m, H-4 ), 2.08 (2H, m, H-5 ), 1.77 (3H, s, H-9 ), 1.60 (3H, s, m, H-3 ), 3.35–3.34 (1H, m, H-5 ), 3.31–3.27 (2H, m, H-2 , H-4 ),

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.66–2.62 (1H, m, H-9), 2.61–2.60 (1H, m, H-5); C-NMR (CD

RSC Advances

1

3

2

3

OD, 500 MHz), d

H

(ppm), J (Hz): 7.70 (1H, d, J ¼ 16.0, H-

0

00

(

1

(

9

7

6

CD OD, 125 MHz), d (ppm): 167.54 (C-9 ), 151.25 (C-4 ), 7 ), 7.49 (2H, d, J ¼ 8.5, H-2 , H-6 ), 6.83 (2H, d, J ¼ 8.5, H-3 , H-

3

C

00

47.85 (C-3 ), 145.74 (C-7 ), 142.39 (C-3), 127.98 (C-1 ), 122.59 5 ), 6.40 (1H, d, J ¼ 16.0, H-8 ), 6.39–6.38 (1H, m, H-3), 5.18 (1H,

0

00

C-6 ), 114.62 (C-8 ), 112.06 (C-2 ), 110.85 (C-5 ), 102.93 (C-4), d, J ¼ 9.5, H-1), 5.04 (1H, d, J ¼ 7.0, H-6), 5.00 (1H, dd, J ¼ 6.0,

0

9.69 (C-1 ), 95.07 (C-1), 81.29 (C-6), 78.66 (C-5 ), 77.70 (C-3 ), 4.0, H-4), 4.81 (1H, overlap, H-1 ), 4.20 (1H, d, J ¼ 13.0, H-10),

0

4.85 (C-2 ), 71.78 (C-4 ), 66.82 (C-8), 62.93 (C-6 ), 61.30 (C-10), 3.95 (1H, dd, J ¼ 12.0, 2.0, H-6 ), 3.87 (1H, d, J ¼ 13.0, H-10),

0

0.27 (C7), 56.41 (4 -OCH

3

), 43.17 (C-9), 36.76 (C-5).

3.72 (1H, br s, H-7), 3.67 (1H, dd, J ¼ 12.0, 6.5, H-6 ), 3.45–

0

3.1.14 Compound 14: specioside. White amorphous 3.42 (1H, m, H-3 ), 3.37–3.35 (1H, m, H-5 ), 3.34–3.27 (2H, m, H-

+

1

0

13

powder, C24

H

28

O

12; (+)-ESI-MS (m/z): 509.1 [M ꢀ H] ; H-NMR 2 , H-4 ), 2.66–2.62 (1H, m, H-9), 2.61–2.59 (1H, m, H-5); C-

ꢁ

Fig. 3 (a) NiCl

2

/MeOH, NaBH

4

, 0 C, 30 minutes, then rt, 1 h; (b) acetic anhydride/Pyr, rt, 12 h; (c) triphenylmethyl chloride/CHCl

3

, Pyr, rt, 12 h; (d)

ꢁ

,2-dimethoxypropane/DMF, TsOH$H O, 50 C; (e) NH OH$HCl/(H O/THF/EtOH) (1 : 1 : 1), TEA, 110 C, 6 h.

2 2 2

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00 00 0 0

C

NMR (CD OD, 125 MHz), d (ppm): 168.61 (C-9 ), 161.39 (C-4 ), 4 ), 66.82 (C-8), 62.92 (C-6 ), 61.29 (C-10), 60.26 (C-7), 43.19 (C-9),

Paper

3

00 00 00 00

1

(

47.20 (C-7 ), 142.36 (C-3), 131.30 (C-2 , C-6 ), 127.08 (C-1 ), 36.74 (C-5).

00

0

16.86 (C-3 C-5 ), 114.61 (C-8 ), 102.94 (C-4), 99.71 (C-1 ), 95.09

3.1.15 Compound 15: catalpol. White amorphous powder,

0 0 0

C-1), 81.30 (C-6), 78.61 (C-5 ), 77.69 (C-3 ), 74.84 (C-2 ), 71.75 (C- C H O ; HR-ESI-MS (m/z): 385.1111 [M + Na] (calculated for

15 22 10

+

Fig. 4 The isolated (1, 2, 10, 13, 14) and synthetic (3–9, 11, 12, 15) iridoid compounds.

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1

15 22 3 H

C H O10Na 385.1089); H-NMR (CD OD, 500 MHz), d (ppm), 3.3. Structural elucidation

J (Hz): 6.36 (1H, dd, J ¼ 6.0, 1.5, H-3), 5.09 (1H, dd, J ¼ 6.0, 4.5,

Elucidations of the structures for compounds 1, 2 and 13, 14

using spectral methods as FT-IR, MS, HR-MS, NMR (1D and 2D)

were reported in ref. 24–29. In-detail data for the character-

isations of each compound is provided in ESI† for in-depth

reference and cross-checking.

0

H-4), 5.06 (1H, d, J ¼ 10.0, H-1), 4.80 (1H, d, J ¼ 8.0, H-1 ), 4.13

0

(

3

7

6

1H, d, J ¼ 13.0, H-10), 3.93 (1H, m, H-6), 3.91 (1H, m, H-6 ), 3.81

1H, d, J ¼ 13.0, H-10), 3.65 (1H, dd, J ¼ 12.0, 6.0, H-6 ), 3.47

0

1H, s, H-7), 3.43 (1H, t, J ¼ 9.0, H-3 ), 3.33 (1H, m, H-5 ), 3.29

0

1H, m, H-4 ), 3.26 (m, H-2 ), 2.55 (1H, dd, J ¼ 9.5, 7.5, H-9), 2.29

1

13

Structural elucidation of compound 10: The H and C NMR

spectra of 10 exhibit typical signals for a catalpol moiety quite

1

3

1H, m, H-5); C-NMR (CD

3

OD, 125 MHz), d

C

(ppm): 141.73 (C-

0

), 104.01 (C-4), 99.70 (C-1 ), 95.30 (C-1), 79.51 (C-6), 78.53 (C-5 ),

7.65 (C-3 ), 74.79 (C-2 ), 71.70 (C-4 ), 66.24 (C-8), 62.84 (C-6 ),

2.57 (C-7), 61.51 (C-10), 43.57 (C-9), 39.05 (C-5).

similar to that of compounds 1, 2, 13 and 14. The side chain

0

13

seems to be a monoterpenoid with ten carbon signals in the

C

NMR spectrum, among them 2,3-substituted double bonds at d

C

00 00 00 00

(

ppm): 144.15 (C-3 ), 138.37 (C-6 ), 128.60 (C-2 ), 125.74 (C-7 ),

0

one ester carbonyl (d

8

1

C

169.34, C-1 ), one oxymethylene (54.37, C-

3.2. Synthesis of catalpol derivatives

0

00

) and two vinylic methyls (d

H

1.77/d

C

12.47: C-9 ; d

H

1.60/d

C

The synthetic derivations are schematically summarised in

Fig. 3. During our investigation on the phytochemical constit-

uents of Dolichandrone spathacea, ve iridoid compounds (1, 2,

00

6.16: C-10 ), the linkage between the side chain and the cata-

lpol moiety is determined as C-6 to C-1 by the correlation of

00

signals at d_C169.34 (C-1 ) to d 4.85 (H-6) in the HMBC spec-

H

10, 13, 14) have been isolated and structural elucidated. Four of

trum. The structure of 10 is elucidated using its 1D and 2D NMR

them (1, 2, 13, 14), with the exception of 10, due to small

amount, were converted into their derivatives by acetylation,

reduction, O-alkylation, acetonisation and hydrolysation to

obtain 3, 4, 5, 6, 7, 8, 9, 11, 12 and 15. Initially, the reduction of

the olen group in cinnamoyl and iridoid moiety in the struc-

ture of 1 and 2 was designed. The reduction was carried out by

spectra. Its ESI-MS spectrum strongly supports this evidence by

+

the pseudomolecular ion peaks at m/z 551.1 [M + Na] and m/z

ꢀ

5

63.0 [M + 2H

2

O–H] in positive and negative mode. In

37

comparison with the reported data, compound 10 is deter-

mined as nemoroside, C25

36 12

H O .

The hydrogenation of the main iridoid components 1 and 2

led to the formation of the dihydro product 3 and 4. The

reduction occurs only at the double bond of cinnamoyl moiety

diﬀerent kind of reductive reagents such as NaBH

4

/MeOH,

LiAlH /MeOH. However, many unwanted products were aﬀor-

4

ded under these condition. This might due to the strong base

condition formed during the working up, causing a damage of

iridoid ring. The trial of reduction with hydrogen catalyzed by

Pd/C did not work, even though the reaction was heated to high

temperature. We therefore used an additional catalyst Lewis

H

of 1 and 2, evidenced by the appearance of two methylene at d /

00

d

C

00

2.91 (t, J ¼ 7.5 Hz, H-7 )/31.15 (C-7 ) and 2.69 (t, J ¼ 7.5 Hz, H-

00

8

)/37.04 (C-8 ) for 3 and 2.93 (t, J ¼ 7.5 Hz, H-7 )/31.60 (C-7 )

00

and 2.72 (t, J ¼ 7.5 Hz, H-8 )/36.96 (C-8 ) for 4. The signals for

acid NiCl

2

$6H

2

O in combination with NaBH

4

reagent. The

ꢁ

reaction was carried out under mild condition at 0 C for 30

minutes. In this case, the products 3, 4 were obtain in good yield

Table 1 Molecular docking simulation results for inhibitory complexes

(83% and 80.6%, respectively). Interestingly, this reductive between the compounds and the protein 3W37 with amino acids: 1-

condition gave regioselective reduction only at olenic bond of 3W37, 2-3W37, 3-3W37, 4-3W37, 5-3W37, 6-3W37, 7-3W37, 8-3W37,

9

-3W37, 10-3W37, 11-3W37, 12-3W37, 13-3W37, 14-3W37, and 15-

cinnamoyl group, but not at the D-3,4-double bond of iridoid

ring. The dihydro derivative 4 was continuously acetylated with

acetic anhydride in pyridine, giving the corresponding pentaa-

cetate 5 in 80% yield. In order to investigate the eﬀect of free

hydroxyl groups on hyperglycemic activity in catalpol iridoids,

compound 2 was O-alkylated with triphenylmethyl chloride and

a

3W37

Ligand–protein complex

Number of interaction

Name

DS

RSMD

Hydrogen bond

van der Waals

1

2

-3W37

ꢀ14.1

ꢀ15.1

ꢀ12.9

ꢀ12.3

ꢀ11.6

—

1.47

1.96

1.33

1.72

1.40

—

1.84

1.76

1.69

1.52

1.46

1.41

1.47

1.01

0.67

7

12

4

6

3

—

6

7

4

7

4

5

14

11

18

—

16

18

9

14

16

18

13

9

compound

TsOH$H

groups were attached only to the primary oxymethylene groups 4-3W37

5-3W37

1

was reacted with 2,2-dimethoxypropane/

2

O to provide product 6 and 9, respectively. The trityl 3-3W37

0

at C-10 in catalpol ring and at C-6 in glucose unit as well. In

6

7

8

-3W37

0

case of 9, cyclic ketal was formed only at C-4 and C-6 of the

ꢀ8.1

glucose unit, due to the steric hindrance of the iridoid and

ꢀ10.5

ꢀ13.3

ꢀ14.7

ꢀ10.1

ꢀ7.8

cinnamoyl moiety. Iridoids 1, 2, 13 and 14 were reacted with 9-3W37

acetic anhydride in pyridine to give the corresponding acetyl 10-3W37

1

1-3W37

2-3W37

3-3W37

4-3W37

products 7, 8, 11 and 12. To nd out the role of cinnamoyl

moiety, this moiety was tried to remove under diﬀerent basic

condition such as NaOH, LiOH, or KOH. However, these

ꢀ8.8

ꢀ13.0

ꢀ12.3

conditions gave many unwanted products. Therefore, an 15-3W37

another milder basic condition using NH OH. HCl in TEA was

a

ꢀ1

2

DS: docking score energy (kcal mol ); RMSD: root-mean-square

applied to obtain the hydrolysation derivative 15 (catalpol) from

compound 2.

_d_e_v_i_a_t_i_o_n₍ _A˚₎_.

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the double bond in the iridoid ring (C-3 and C-4) are still six acetyl groups corresponding to the acetylation of six hydroxyl

remained in the NMR spectra of 3 and 4. Compound 5 was the groups in their structures. The cleavage of the cinnamoyl moiety

acetylated product of 4. Five acetyl groups are formed in the is determined by the disappearance of the signal of cinnamoyl

structure of 5, deducing by the appearance of ve acetyl methyl group in the NMR spectra of 15. The higheld chemical shi of

singlet at d

0.54, 20.57, 20.71, 20.75 as well as the observation of ve

carbonyl groups at d 172.64, 172.45, 171.60, 171.14, 170.92. aer hydrolysation.

Similarly, the totally acetylation of hydroxyl groups in 11 and 8 All the elucidated structural formulae are presented in Fig. 4.

H

/d

C

H C

2.00, 2.03, 2.04, 2.10, 2.13 (each 3H, s)/20.51, H-6/C-6 at d /d 3.93/79.51, compared to those of 2 (H-6/C-6 at

2

d

H

C

/d 5.05–5.00/79.65), is due to the free hydroxyl group forming

C

is conrmed by the signals of ve acetyl groups in the NMR To the best of our knowledge, the structures elucidated

spectra of these compounds. NMR spectra of 7 and 12 indicate regarding compounds 3, 4, 5, 6, and 9 are in respect of new

Fig. 5 Visual presentation and in-pose interaction map of ligand-3W37 inhibitory complexes: (A) 1-3W37, (B) 2-3W37, (C) 3-3W37, (D) 4-3W37,

(

E) 5-3W37, (F) 9-3W37, (G) 10-3W37, (H) 14-3W37, and (I) 15-3W37.

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semi-synthesised iridoid-derivatives that found having unre- (3W37 and 3AJ7) was simulated by molecular docking tech-

ported in the literature, given our reachable referencing. The nique. List of descriptive symbols are given in ESI† (Section 2.3).

HR-ESIMS spectra of all the new synthetic compounds in

Overall, preliminary screening groups all the iridoid

Section 3.1 (characterisation) also further conrmed the eluci- compounds into two inhibitability-based categories; in detail, 1,

dation of their structure.

2, 3, 4, 5, 9, 10, 14, and 15 are considered performing elevated

inhibitory eﬀects in comparison to those of 6, 7, 8, 11, 12, and

1

3

3. This is regardless of the targeted proteins, either 3W37 or

AJ7. The justication is due to referencing of corresponding

3

.4. Simulation of enzyme inhibitability

simulations on selected commercial drugs D1, D2, and D3.

.4.1 Molecular docking simulation for iridoid-3W37.

Regarding 1, 2, 3, 4, 5, 9, 10, 14, and 15, the docking results

3

Static interaction between the studied inhibitory agents (iridoid

compounds and referenced drugs) and the targeted proteins

Fig. 6 Visual presentation and in-pose interaction map of ligand-3W37 inhibitory complexes: (A) 1-3AJ7, (B) 2-3AJ7, (C) 3-3AJ7, (D) 4-3AJ7, (E)

-3AJ7, (F) 9-3AJ7, (G) 10-3AJ7, (H) 14-3AJ7, and (I) 15-3AJ7.

5

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related to their inhibitory complexes with protein 3W37 are towards the protein. The respective calculated RMSD varies

˚

summarised in Table 1 (in-detail parameters included in ESI† – between 1.41 and 1.84 A, acceptable values for a rm confor-

Section 2.4) and the complex structures are virtually represented mation. Furthermore, in-depth results of the inhibitory

in Fig. 5. The former provides inhibition parameters (DS value complexes are also summarised in Table 1 while their corre-

and RMSD), and in-depth bonding details building up the host sponding 3D- and 2D-virtual renderings are included in ESI†

complexes; while, the latter visualises the optimised orientation (Section 2.1). In exceptional, 6 was found not able to perform

of each ligand in an active site of protein 3W37. DS value for 2- inhibition towards protein 3W37.

ꢀ

1

3

W37 registers ꢀ15.1 kcal mol , the lowest value calculated.

3.4.2 Molecular docking simulation for iridoid-3AJ7.

This means the complex is at the lowest free-energy level, Regarding 1, 2, 3, 4, 5, 9, 10, 14, and 15, their inhibitory

thereby most stable. In detail, compound 2 seems to exhibit complexes with protein 3AJ7 are virtually presented in Fig. 6 and

great aﬃnity with a specic amino acid in 3W37 structure, aka. their respective docking results are summarised in Table 2 (in-

arginine, by creating seven ionic and four H-acceptor bonds detail parameters included in ESI† – Section 2.4). The former

with four diﬀerent arginine molecule, i.e. Arg 814, Arg 670, Arg predicts the ligand conformation and orientation in an active

6

76, and Arg 699, and one ionic bond with Asp 666. They alto- site of the protein; while, the latter provides in-depth docking

ꢀ

1

gether compose ꢀ39.2 kcal mol in respect of hydrophilic parameters of the complexes, including DS value, RMSD, and

˚

attraction, of which bonding lengths are in 2.78–3.95 A. This interaction detail. The highest DS value obtained is

ꢀ

1

stability is followed by those of 10-3W37 and 1-3W37 with the ꢀ14.5 kcal mol , responsible for the stability of 14-3AJ7 by

ꢀ1

DS values ꢀ14.7 and ꢀ14.1 kcal mol , respectively, both representing the lowest free-energy level. However, there are

composed by seven hydrogen bonds to a variety of amino acid only ve hydrophilic interactions detected as the complex

types. However, their hydrophilic energy distribution sees forms, including four ionic and one H-donor bonds. The tar-

diﬀerent patterns. While each 10-3W37 ligand–amino acid geted amino acids are aspartic acid (Asp 242, Asp 352) and

hydrogen bond contributes rather evenly to the total hydro- glutamic acid (Glu 277), which create hydrogen-bond binding

ꢀ

1

˚

philic free energy of ꢀ11.9 kcal mol , C-Agr 670 H-acceptor with 14 carbon atoms in distance 2.93–3.82 A. The total

ꢀ1

bonding holds ꢀ8.7 kcal mol of free energy accounting for hydrophilic potential calculated is ꢀ9.9 kcal mol , insigni-

ꢀ

1

over a ha of 1-3W37 total gure, ꢀ17.2 kcal mol . The former cantly. Hence, 14-3AJ7 stability seems accumulated from van

˚

contains the binding performances in distance 2.71–3.30 A, der Waals forces arisen between its two components as they

while the corresponding gures for the latter are slightly include twenty diﬀerent 3AJ7 amino acids in involvement. This

˚

elevated, i.e. 2.75–3.80 A. This also justies the slight out- is followed by 2-3AJ7 of which stability is expressed via

ꢀ

1

weighing of 10-3W37 stability, previously evaluated by DS ꢀ13.5 kcal mol of DS value. The value is likely cultivated from

values. On the other hand, hydrophobic binding contributes both hydrophilic and hydrophobic contribution. There are nine

fourteen van der Waals interactions to each 2-3W37, 10-3W37 or hydrogen bonds formed between molecule 2 and 3AJ7 amino

ꢀ1

˚

1

3

-3W37 inhibitory structure. Otherwise, 3-3W37, 4-3W37, 5- acids in distance 2.58–4.0 A, accounting for ꢀ28.8 kcal mol of

W37, 9-3W37, 14-3W37, and 15-3W37 seem less stable given

their inferior DS values, i.e. ꢀ12.9, ꢀ12.3, ꢀ11.6, ꢀ13.3, ꢀ13.0,

ꢀ

1

and ꢀ12.3 kcal mol . Therefore, the inhibitability of the Table 2 Molecular docking simulation results for inhibitory complexes

regarded compounds accords with an order: 2 > 10 > 1 > 9 > 14 > between the compounds and the protein 3AJ7 with amino acids: 1-

3

AJ7, 2-3AJ7, 3-3AJ7, 4-3AJ7, 5-3AJ7, 6-3AJ7, 7-3AJ7, 8-3AJ7, 9-

AJ7, 10-3AJ7, 11-3AJ7, 12-3AJ7, 13-3AJ7, 14-3AJ7, and 15-3AJ7

˚

3

> 4 ¼ 15 > 5. In addition, all RMSD values registering under 2 A

a

indicates that the associated complexes are tolerable as bio-

logical rigid bodies. In particular, although exhibiting

a moderate DS value, the average distance between neigh-

bouring atoms in 15-3W37 structure is signicantly short given

Ligand–protein complex

Number of interaction

Name

DS

RSMD

Hydrogen bond

van der Waals

˚

its RMSD value of 0.67 A. This suggests a ligand-bound

1

2

-3AJ7

ꢀ11.4

ꢀ13.5

ꢀ10.6

ꢀ10.2

ꢀ11.7

—

1.14

1.64

1.71

1.79

1.80

—

1.98

1.90

1.74

1.33

1.99

1.06

1.99

1.71

1.12

7

9

8

6

4

—

3

4

7

4

6

4

5

3

20

15

16

15

22

—

22

20

17

21

15

32

27

20

10

conformation if the inhibitory structure is formed. The reason

might relate to ligand-pose spatial complementarity. Also, 3-3AJ7

illustrative description for the intermolecular interactions 4-3AJ7

detected in each active site is projected on a 2D diagram for

each complex. It is also clear that all iridoid ligands are in high

exposure to their targeted protein shown by densely blurred-

violet zones, while long and continuous proximity contour 9-3AJ7

bounding large in-pose areas likely indicate unintermittent 10-3AJ7

5

6

7

8

-3AJ7

ꢀ9.3

ꢀ8.8

ꢀ11.5

ꢀ12.4

ꢀ6.3

1

1-3AJ7

2-3AJ7

3-3AJ7

4-3AJ7

interactability between the docking agents. Finally, visual

observations reinforce the inhibitability since the docked sites

are still spacious aer the inhibition of 1, 2, 3, 4, 5, 9, 10, 14, or

ꢀ6.4

ꢀ7.5

ꢀ14.5

ꢀ11.0

15.

15-3AJ7

In respect of 7, 8, 11, 12, and 13, DS values associated with

their ligand-3W37 inhibitory complexes register over

10.5 kcal mol , thus deemed as less competent inhibitors

a

ꢀ1

DS: docking score energy (kcal mol ); RMSD: root-mean-square

_d_e_v_i_a_t_i_o_n₍ _A˚₎_.

ꢀ

1

ꢀ

11970 | RSC Adv., 2021, 11, 11959–11975

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the former free energy; while, the latter is from van der Waals

In respect of 7, 8, 11, 12, and 13, DS values associated with

attraction constituted by een diﬀerent in-pose amino acids. their ligand-3AJ7 inhibitory complexes are also included in

In contrast, 10-3AJ7 binding aﬃnity is likely based more on Table 2. The respective gures are ꢀ9.3, ꢀ8.8, ꢀ6.4, and

ꢀ1

hydrophobic interactions than on hydrophilic counterparts as ꢀ7.5 kcal mol , clearly expressing inferiority of overall

˚

the former includes twenty-one amino acids while the latter stability. Their RMSD values are all under 1.99 A. Also, their

ꢀ

1

results in a total energy just ꢀ7.5 kcal mol . Its DS value corresponding 3D morphology and 2D interaction map are

ꢀ

1

registers ꢀ12.4 kcal mol , the third highest gure. Otherwise, given in ESI† (Section 2.2). Similar to investigation on ligand-

DS values of 1-3AJ7, 3-3AJ7, 4-3AJ7, 5-3AJ7, 9-3AJ7, and 15-3AJ7 3W37, failure was also recorded in an attempt to establish

ꢀ

1

are ꢀ11.4, ꢀ10.6, ꢀ10.2, ꢀ11.7, ꢀ11.5, and ꢀ11.0 kcal mol

,

a 6-3AJ7 inhibitory structure. No possible intermolecular

respectively. Therefore, the ligand inhibitability towards protein interaction is given, thus no inhibitability of molecule 6 towards

3

AJ7 follows an order: 14 > 2 > 10 > 5 > 1 ¼ 9 > 15 > 3 > 4. In protein 3AJ7 ensuing. The reason for both could be referred to

˚

addition, by possessing RMSD value under 2 A, all the inhibitory spatial restraint due to 6 structural bulkiness and branching,

complexes are accepted performing biological rigidity. More- which possibly prohibit its entry into the host active site.

over, visual illustration of interacting activity between the However, more in-depth investigations, either theoretical or

ligand and in-pose amino acids clarify the predominance of experimental, are needed to reach a more accurate conclusion.

hydrophobic interactions in the establishment of ligand-3AJ7

3.4.3 Molecular docking simulation for drug–protein

inhibitory structures. This is justied by a myriad of amino complexes. The inhibitability of three commercial medicines

acids presenting around the docked compounds. Resembling to acarbose (D1), miglitol (D2), and voglibose (D3) towards the

observations on ligand-3W37, spaciousness inside the active carbohydrate-hydrolase proteins (3W37 and 3AJ7) were investi-

sites are highly conducive to motion of 1, 2, 3, 4, 5, 9, 10, 14, or gated for referencing purposes. The inhibitions are virtually

15 when inhibition processes are on, thus their inhibitability rendered in Fig. 7, while in-detail docking results are sum-

towards protein 3AJ7 aﬃrmed. marised in Table 3 (in-detail parameters included in ESI† –

Fig. 7 Visual presentation and in-pose interaction map of ligand-protein inhibitory complexes: (A) D1-3W37, (B) D2-3W37, (C) D3-3W37, (D) D1-

W37, (E) D2-3AJ7, and (F) D3-3AJ7.

3

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Table 3 Molecular docking simulation results for inhibitory complexes Nevertheless, these complexes are considered possessing

between the drugs and the two protein 3W37, 3AJ7 with amino acids:

ligand-bound conformations given their short average distance

a

D1-3W37, D2-3W37, D3-3W37; D1-3AJ7, D2-3AJ7, and D3-3AJ7

between in-active atoms represented by RMSD of 0.68 and 1.03

˚

A. Other RMSD values register under 2 A and most binding

Ligand–protein complex

Number of interaction

˚

length are predicted under 3 A. The inhibitability of the medi-

Name

DS

RSMD

Hydrogen bond

van der Waals

cines towards carbohydrate-hydrolase proteins (3W37 and 3AJ7)

can be briefed as: acarbose (D1) > voglibose (D3) > miglitol (D2).

In referencing, there are no signicant diﬀerentials of the

inhibitory indicators between these commercial medicines and

the selective iridoid compounds. This implies promising

applicability of these substances as carbohydrate-hydrolase

inhibitors in particular and in diabetes treatment in general.

D1-3W37

D2-3W37

D3-3W37

D1-3AJ7

D2-3AJ7

D3-3AJ7

ꢀ14.2

ꢀ11.1

ꢀ12.7

ꢀ15.3

ꢀ10.7

ꢀ13.6

1.58

0.68

1.52

1.79

1.03

0.94

8

5

14

8

6

9

5

10

20

8

12

a

ꢀ1

DS: docking score energy (kcal mol ); RMSD: root-mean-square 1, 2, 10 regarding 3W37 inhibition and 2, 10, 14 regarding 3AJ7

deviation (A^˚ ).

inhibition are even highly competent.

3.5. Screening of physicochemical and pharmaceutical

compatibility

Section 2.4). All drugs seem fully tting with their inhibiting

structural topography given their continuous proximity

contours. This indicates high degree of complementarity. Even

quasi-macromolecule D1 still fulls this topographical tting.

However, diﬀerent duo-systems see diﬀerent patterns of inter-

molecular interaction between the adducts. In particular, D1 is

able to create a myriad of interactions with its in-pose amino

acids regardless of either the host protein or types of binding,

thus conducive to its prominent inhibitability in comparison to

the others. DS values of D1-3W37 and D1-3AJ7 are ꢀ14.2 and

Several properties of studied ligands are summarised in Table 4

in order to screen their physicochemical and pharmaceutical

compatibility based on Lipinski's rule of ve. The most prom-

ising candidates, aka. 1, 2, and 10, weigh ca. 500 amu and

possess negative dispersion coeﬃcients (log P and log S). Only

1

0 creates less than both ten hydrogen bond acceptors and ve

hydrogen bond donors regardless of the targeted protein, either

W37 or 3AJ7. This preliminarily suggests 10 as the most

3

potential compound for oral administration in attempt to tackle

diabetes. However, other promising candidates should be in

great consideration. First, 507.1 amu 14 might still be suitable

since the commercial product Acarbose weigh 645.6 amu, over

Lipinski's rst criterion. The highly eﬃcacy-demonstrated

medicine also forms seven hydrogen bond donor with protein

ꢀ

1

ꢀ

15.3 kcal mol , respectively. These were followed by the

corresponding gures for D3-protein structures, i.e. ꢀ12.7 and

ꢀ

1

ꢀ

13.6 kcal mol , respectively. Calculation on D2-protein

inhibition results in relatively inferior DS values, i.e.

1.1 kcal mol for D2-3W37 and ꢀ10.7 kcal mol for D2-3AJ7.

ꢀ1

1

ꢀ1

Table 4 Summarisation of physiochemical properties of studied compounds including docking score energy values (DS, kcal mol ), molecular

3

mass (M

a

, amu), polarizability ( A˚ ), volume or size ( A˚ ), log P, log S and the total of hydrogen bonds of the 15 potential substances docked with the

two proteins 3W37 and 3AJ7

Dispersion

coeﬃcients

Hydrogen bond (3W37/

3AJ7)

Compound (ligand)

DS

Mass

Polarizability

Volume

Log P

Log S

H-acceptor

H-donor

1

2

3

4

5

6

7

8

9

ꢀ12.8

ꢀ14.3

ꢀ11.8

ꢀ11.3

ꢀ11.7

0.0

522.5

552.5

524.5

554.5

764.7

1037.2

790.7

762.7

562.6

528.6

732.3

760.2

538.0

508.4

362.3

645.6

207.2

267.3

49.3

51.8

45.3

50.7

49.6

29.3

33.8

37.2

48.4

51.1

31.5

32.7

32.1

47.4

31.4

60.9

20.8

26.0

559.5

595.3

561.2

593.9

814.6

1105.6

832.7

810.7

604.5

568.1

785.1

868.9

801.8

518.7

162.5

613.9

235.9

280.8

0.8

1.2

1.1

1.5

1.8

10.4

1.9

2.1

1.0

1.2

2.4

1.8

2.0

2.1

3.4

2.7

2.3

ꢀ2.0

ꢀ1.8

ꢀ1.6

ꢀ1.5

ꢀ4.8

ꢀ13.8

ꢀ5.2

ꢀ5.1

ꢀ3.4

ꢀ1.4

ꢀ5.3

ꢀ5.4

ꢀ4.9

ꢀ0.9

ꢀ0.8

ꢀ0.5

ꢀ0.2

4/1

4/2

3/1

4/2

3/4

0/0

4/1

3/1

2/1

2/2

2/1

3/2

2/1

1/0

4/1

5/0

3/1

3/2

2/6

0/6

1/6

2/4

0/0

0/1

0/0

1/1

2/3

0/2

1/0

0/2

0/1

1/2

3/7

2/3

3/6

ꢀ8.7

ꢀ9.7

ꢀ12.4

ꢀ13.6

ꢀ8.2

10

11

12

13

14

15

ꢀ7.1

ꢀ8.2

ꢀ13.8

ꢀ11.7

ꢀ14.8

ꢀ10.9

ꢀ13.2

D1

D2

D3

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3

AJ7. This justies the applicability of 1 and 2. In addition, it is pose topographical tting. However, in-depth investigations

3

˚

noticeable that their polarisability is over 10 A , indicating high are still required in order to reach more accurate view. Although

polarisation. The property is of signicance because it is highly predicted exhibiting insignicant inhibitability towards a-

conducive to protein inhibition as the polypeptide molecule is glucosidase molecule (3W37) by molecular docking simulation,

made of polarised amino acids. Therefore, the selective iridoid experimental results reect otherwise. On the other hand, 9 also

compounds, especially 10, are likely compatible with pharma- sees noticeable simulation-experiment inconsistency, in which

ceutical applications in physiological medium. However, in vitro the compound is expected to perform pronounced a-glucosi-

and in vivo experiments are required in order to conrm the dase inhibition.

00

computational predictions.

Compounds 3, 4, and 5, without double bond at C-7 and C-

0

In summary, the results obtained altogether are likely to 8 , are inactive towards a-glucosidase observed from enzyme

justify the applicability of the novel-synthesised iridoid assays. This is relatively consistent with the computational

compounds in cytological in general, and for inhibition of prediction as these compounds are not expected to be eﬀective

carbohydrate-hydrolase proteins (3W37 and 3AJ7) in particular. 3W37 inhibitors by the simulation. Therefore, double bond at

0

00

C-7 and C-8 could be subjected for further investigations on a-

glucosidase inhibition. Regarding acetylation, the correspond-

ing derivatives are either inactive including 8 and 11, or

unfavoured such as 7 (IC50 167.76 mM) and 12 (IC50 71.56 mM) as

a-glucosidase inhibitors. The corresponding computing also

predicts this unfavourableness. The lessening of polarity,

caused by total acetyl-hydroxyl substitution, might reason this,

thus justifying the important role of catalpol hydroxyl groups to

the inhibition. In addition, computationally expected possess-

ing no inhibitability towards 3W37, 6 performs assaying inhi-

bition towards a-glucosidase with a notably high IC50 value of

3

.6. a-Glucosidase inhibition

The enzyme inhibitory activity of fourteen compounds

excluding 15) were assayed towards a-glucosidase. Acarbose

was used as a reference whose IC₅₀is determined registering

85.00 mM in the resembling assay conditions. The obtained

(

2

results are shown in Table 5, which are relatively consistent with

those predicted by computational simulation. In detail, 10 > 2 >

14 > 13 > 1 assemble the most eﬀective inhibitors towards a-

glucosidase whose attained IC50 values register lower than 25

mM. Compound 10 shows its marked inhibition towards the

enzyme with an IC50 value of 0.05 mM, higher than that of

acarbose by 5700 times. This was followed by 2 and 14, both

exhibiting signicant a-glucosidase inhibition with IC₅₀value

2

24.78 mM. This reinforces the implication that two bulky tri-

0

phenyl methyl groups at C-10 and C-6 seem to limit the host-

molecule entrance into the protein sites.

From the obtained results, several brief views on structural

activity relationship of iridoid catalpol derivatives on a-gluco-

sidase inhibition can be speculated. Acetylation of the hydroxyl

groups at C-10 and glucose unit leads to reduced activity.

Reduction of the double bond in the cinnamoyl moiety as well

7.24 and 8.65 mM, respectively. The corresponding gure for 13

is 20.84 mM and for 1 is 24.89 mM. The predominance of 10

inhibitability seems signifying the role of (2E,6E)-8-hydroxy-2,6-

dimethyl-2,6-octadienoate moiety as it is the only compound

containing this functional group. Its exibility and polarity

acquired from an octadienoate conguration might be advan-

tageous to structural transformation, which in turn conducive

to either protein-site entrance, polar–polar interaction, or in-

0

as locking the hydroxyl groups at C-6 and C-4 of the glucose

unit by a cyclic acetal group totally deteriorate the activity. The

0

presence of a hydroxyl group at C-4 of cinnamoyl moiety is

likely to play an important role of activity, much better than the

corresponding property for methoxy or acetyl group. The

attachment of two bulky triphenylmethyl groups at C-10 and C-

0

Table 5 Experimental a-glucosidase inhibitory activity of catalpol 6 strongly reduces the activity, 32-fold decrease of inhibition.

a

iridoids

Finally, the location of a long, linear unsaturated alkyl ester

chain at C-6 (octadienonate) instead of cinnamoyl moiety

signicantly rises the a-glucosidase inhibitory activity. Nem-

^o^r^o^sⁱ^d^e⁽¹⁰⁾ⁱ^s^t^h^e^m^o^s^t^a^c^tⁱ^v^e^c^o^m^p^o^uⁿ^d^wⁱ^t^h^aⁿ^I^C50 value of

0.05 mM, 5.700 times better than acarbose. This could be

explained by the exibility of its bonding structure, thus

conducive to its topological tness while inside the inhibitory

holes.

Compound

IC50 (mM)

1

2

3

4

5

6

7

8

9

24.89

7.24

NA

224.78

167.76

NA

4. Conclusions

NA

1

0

1

2

3

4

0.05

NA

71.56

20.84

8.65

285.00

This study suggests a promising approach to the use of iridoid

chemotype from Dolichandrone spathaceae as a-glucosidase

(protein 3W37) and oligo-1,6-glucosidase (protein 3AJ7) inhibi-

tors. Five isolated natural iridoids and ten synthetic derivatives

were successfully identied by structural elucidation. These

include ve new iridoid-derived structures not found having

reported before in the literature, i.e. 3, 4, 5, 6, and 9. Molecular

Arcabose (D1)

a

NA: no activity (IC50 > 390 mM).

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docking simulation indicates that 1, 2, 3, 4, 5, 9, 10, 14, and 15

could perform elevated inhibitability towards both

carbohydrate-hydrolase proteins. Regarding protein 3W37, ve

strongest predicted inhibitors accords with an order assemble 2

6 Z. Sun and C. A. Henson, Degradation of native starch

granules by barley a-glucosidases, Plant Physiol., 1990, 94,

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7 H. Matsui, S. Chiba and T. Shimomura, Substrate specicity

of an a-glucosidase in sugar beet seed, Agric. Biol. Chem.,

1978, 42, 1855–1860, DOI: 10.1080/00021369.1978.10863265.

8 H. Taniguchi and Y. Honnda, Amylases, Encyclopedia of

Microbiology, 2009, pp. 159–173.

ꢀ

1

ꢀ1

(

DS – 15.1 kcal mol ) > 10 (DS – 14.7 kcal mol ) > 1 (DS –

4.1 kcal mol ) > 9 (DS – 13.3 kcal mol ) > 14 (DS –

ꢀ

1

ꢀ1

1

ꢀ

1

3.0 kcal mol ). In respect to 3AJ7, the corresponding order is

ꢀ

1

ꢀ1

4 (DS – 14.5 kcal mol ) > 2 (DS – 13.5 kcal mol ) > 10 (DS –

ꢀ

1

ꢀ1

2.4 kcal mol ) > 5 (DS – 11.7 kcal mol ) > 1 ¼ 9 (DS –

9 K. Watanabe, Y. Hata, H. Kizaki, Y. Katsube and Y. Suzuki,

The rened crystal structure of Bacillus cereus oligo-1,6-

ꢀ

1

1.5 kcal mol ). Exceptionally, compound 6 is predicted

˚

unable to establish an inhibitory structure with any given

proteins. Lipinski's rule of ve suggests 10 as the most potential

candidate for oral administration; while, 1, 2, and 14 are highly

promising for pharmaceutical applications in physiological

glucosidase at 2.0 A resolution: Structural characterization

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proline-substitution

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suitable for inhibition of polarised protein molecules. Enzyme

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eﬀective inhibitor with an IC₅₀value of 0.05 mM, higher than

intestinal plasma membrane: Posttranslational route and

cleavage of sucrase-isomaltase, Proc. Natl. Acad. Sci. U. S.

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in the order 10 (IC₅₀0.05 mM) > 2 (IC₅₀7.24 mM) > 14 (IC₅₀8.65

mM) > 13 (IC50 20.84 mM) > 1 (IC50 24.89 mM), showing good

consistency with the docking-based predictions and signicant

A. D. Andricopulo, Molecular docking and structure-based

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molecules200713384.

predominant in comparison to acarbose (IC50 285.00 mM). 12 I. M. Kapetanovic, Computer-aided drug discovery and

Compound 6 performs unfavoured inhibitability in the in vitro

bioassay with IC50 value of 224.78 mM. The results are consid-

ered highly advantageous to preparation of therapeutic medi-

development (CADDD): In silico-chemico-biological

approach, Chem.-Biol. Interact., 2008, 171, 165–176, DOI:

10.1016/j.cbi.2006.12.006.

cines based on iridoid chemotype in an attempt to develop an 13 T. M. Chandra Babu, S. S. Rajesh, B. V. Bhaskar, S. Devi,

alternative for diabetes treatment.

A. Rammohan, T. Sivaraman and W. Rajendra, Molecular

docking, molecular dynamics simulation, biological

evaluation and 2D QSAR analysis of avonoids from

Syzygium alternifolium as potent anti-Helicobacter pylori

agents, RSC Adv., 2017, 7, 18277–18292, DOI: 10.1039/

c6ra27872h.

Conﬂicts of interest

There are no potential conicts of interest by the authors.

1

4 T. Du Ngo, T. D. Tran, M. T. Le and K. M. Thai,

Computational predictive models for P-glycoprotein

inhibition of in-house chalcone derivatives and drug-bank

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Acknowledgements

The authors are grateful to Vietnam Academy of Science and

Technology (VAST) for nancial support (Project Nr: VAST04.03/

10.1007/s11030-016-9688-5.

19–20). The authors also acknowledge the partial support of

5 K. M. Thai, D. P. Le, N. V. K. Tran, T. T. H. Nguyen, T. D. Tran

and M. T. Le, Computational assay of Zanamivir binding

aﬃnity with original and mutant inuenza neuraminidase

Hue University under the Core Research Program, Grant No.

NCM. DHH.2020.04.

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9, DOI: 10.1016/j.jtbi.2015.08.019.

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RSC Adv., 2021, 11, 11959–11975 | 11975

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Isolation, semi-synthesis, docking-based prediction, and bioassay-based activity ofDolichandrone spathaceairidoids: new catalpol derivatives as glucosidase inhibitors

DOI: 10.1039/d1ra00441g

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Article abstract of DOI:10.1039/d1ra00441g

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