Elsevier

Bioorganic & Medicinal Chemistry

Volume 17, Issue 4, 15 February 2009, Pages 1464-1473
Bioorganic & Medicinal Chemistry

Stereoselective synthesis of bioactive isosteviol derivatives as α-glucosidase inhibitors

https://doi.org/10.1016/j.bmc.2009.01.017Get rights and content

Abstract

Considerable interest has been attracted in isosteviol and its derivatives because of their large variety of pharmacological activities. In this project, a series of novel compounds containing hydroxyl, hydroxymethyl group and heteroatom-containing frameworks fused with isosteviol structure were synthesized and evaluated as α-glucosidase inhibitors, aimed at clarifying the structure–activity correlation. The results indicated that these isosteviol derivatives were capable of inhibiting in vitro α-glucosidase with moderate to good activities. Among them, indole derivative 15b exhibited the highest activities and thus may be exploitable as a lead compound for the development of potent α-glucosidase inhibitors.

Graphical abstract

A novel series of isosteviol derivatives were designed and prepared. Within all compounds, 15b (IC50 = 68.2 μM) showed the most potent inhibitory activities against α-glucosidase.

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Introduction

During the last few decades, there has been widespread interest in α-glucosidase (EC 3.2.1.20) because of its important role not only in carbohydrate digestion, but also in the processing of glucoproteins and glycolipids. In addition, the α-glycosidase inhibitors have wide application for treatment of carbohydrate mediated diseases such as diabetes,1, 2, 3 cancer,4, 5 HIV6 and certain forms of hyperlipoproteinemia and obesity.7 Therefore, considerable endeavors have been made to develop inhibitors that can probe the structure and function of α-glycosidase.8, 9 To date, various types of inhibitors have also been designed based on the structures that resemble the glycosyl cations in a transition state of hydrolysis by glucosidase.10

Isosteviol (ent-16-ketobeyeran-19-oic acid 1) is a tetracyclic diterpenoid with a beyerane skeleton, obtained by acid hydrolysis of stevioside.11, 12 In recent years, isosteviol derivatives have attracted scientific attention because of their remarkably broad spectrum of biological activities including antihypertension,13 anti-inflammatory,14 glucocorticoid agonist,15 antiproliferation,16 antitumor17 and inhibition of ent-kaurene synthase.18 Especially, Wang and co-workers reported that isosteviol can decrease the blood glucose concentration in Zucker diabetic fatty rats,19 which prompted us to study isosteviol derivatives to develop new α-glucosidase inhibitors for the treatment of diabetes.

In this study, a series of novel isosteviol derivatives were synthesized by a facile route, and the α-glucosidase inhibition activities of the derivatives were appraised, which would be aiding in designing and synthesizing novel stronger α-glucosidase inhibitors and clarifying the structure–activity correlation involved in the inhibition process of α-glucosidase.

Section snippets

Results and discussion

In order to find a lead compound, 29 were designed and synthesized with isosteviol as starting material (Scheme 1). Initial synthetic efforts were focused on structural modifications at C-15 and C-16 positions of isosteviol 1. Treatment of isosteviol obtained by acid hydrolysis of stevioside with CH3CH2Br and KOH in DMSO afforded the corresponding ethyl ester of isosteviol 2 in 96% yield.20 Compounds 3 and 4 were obtained, respectively, in good yields by reduction of 1 and 2 with NaBH4 in C2H5

Conclusion

In summary, a series of novel compounds containing hydroxyl, hydroxymethyl group and heteroatom-containing frameworks fused with isosteviol structure have been successfully synthesized in high yields, and their inhibitory activities against α-glucosidase were evaluated. The results obtained revealed that these isosteviol derivatives were capable of inhibiting α-glucosidase with moderate to good activities, indicating that structural modification of isosteviol is a practical approach to increase

General methods

All reagents and solvents were obtained from commercial suppliers. All the reactions were monitored by TLC. Melting points were determined on a Beijing Keyi XT5 apparatus and the temperature was not corrected. IR spectra were recorded as KBr pellets on a Thermo Nicolet (IR200) Spectrometer. 1H and 13C NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400 and 100 MHz with TMS as internal standard. Mass spectra were taken by Waters Q-Tof micro mass spectrometer. X-ray analysis was

Acknowledgment

The authors are grateful for the financial support to the National Natural Science Foundation of China (Project No. 20772113).

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