Elsevier

Bioorganic & Medicinal Chemistry

Volume 16, Issue 24, 15 December 2008, Pages 10198-10204
Bioorganic & Medicinal Chemistry

Synthesis and biological evaluation of a 2-aryl polyhydroxylated pyrrolidine alkaloid-based library

https://doi.org/10.1016/j.bmc.2008.10.063Get rights and content

Abstract

Inspired by polyhydroxylated pyrrolidine alkaloid natural products, a 18-membered library of 2-aryl polyhydroxylated pyrrolidines has been efficiently prepared in two or three synthetic steps from the known chiral cyclic nitrones with high yield and purity and excellent stereoselectivity. The inhibitory activity of all these compounds against various glycosidase enzymes was evaluated. Interestingly, 15 and 19 show better inhibitory activities than radicamine A (20) and B (18) against α-glucosidases. The IC50 values of 15 and 19 are 1.1 and 0.5 μM, respectively. In this study, we also discovered the substituent(s) on the aryl ring could affect the inhibition potency and selectivity against glycosidases.

Introduction

Naturally occurring polyhydroxylated pyrrolidines impart a variety of biological activities including glycosidase inhibition, antiviral activity, and antidiabetic activity.1, 2 A new class of polyhydroxylated pyrrolidines was recently discovered, in which an aryl moiety was found to be directly attached to the C-2 position of the pyrrolidine ring (Fig. 1).3, 4, 5 Members of this class include (−)-codonopsinine and (−)-codonopsine, both isolated from Codonopsis clematidea (a herb used in folk medicine to improve hepatic function), and were found to exhibit antibiotic activity and hypotensive activity without affecting the central nervous system.3 Recently, another new alkaloid, codonopsinol, was reported by Ishida et al.,4 and in 2001, Kusano and co-workers first isolated radicamines A and B from Lobelia chinensis Lour, an important herb prescribed in traditional Chinese medicine as a diuretic, antidote, and carcinostatic agent. Radicamines A and B were subsequently shown to be new glycosidase inhibitors.5 From a structural point of view, the absolute configurations of these molecules are (2R,3R,4R,5R) or (2S,3S,4S,5S) at the four stereogenic centers and the relative stereochemistry of the substituents at C2, C3 is trans (Fig. 1). The interesting structures of these molecules and their potentially useful biological activity have inspired the total synthesis of specific targets6, 7 and, in the cases of radicamines A and B, revision of their absolute configurations of these nature products.8, 9

Our research interests include the design and synthesis of natural product-based small molecule libraries via a combinatorial approach.10 Clearly, the variety of biological activities exhibited by molecules containing the 2-aryl pyrrolidine skeleton suggests this motif to be a privileged scaffold of potential use in combinatorial chemistry for drug discovery.11 Meanwhile, recent reports show that the enantiomers of natural products or synthetic bioactive molecules, such as l-nucleoside analogues or l-iminocyclitols, may possess interesting or unexpected biological activity.12, 13 To the best of our knowledge, however, use of the 2-aryl pyrrolidine skeleton as a privileged scaffold in combinatorial chemistry for the synthesis of both enantiomers of various derivatives bearing substituents on the aryl ring and the nitrogen atom of the pyrrolidine ring has not been completely explored.

Herein, we describe the preparation of a small molecule library based on a general 2-aryl polyhydroxylated pyrrolidine core structure with two points of substitution diversity (R1 and R2 in 1, see Fig. 2). In addition, the enantiomeric library 2 was also prepared (structural diversity).14 The inhibitory activity of these molecules against various glycosidases was also examined.

Section snippets

Design and strategy

The stereoselective addition of a nucleophile to a chiral cyclic nitrone to give a polyhydroxylated pyrrolidine has been reported by Goti, Gurjar, Yu, and others.6, 8, 15 In this approach, a Grignard reagent attacks a cyclic nitrone16 on the less hindered face opposite to that of the neighboring benzyl ether group to give a product having a 2,3-trans configuration (Scheme 1). A common structural feature of alkaloid libraries 1 and 2 is the 2,3-trans configuration (Fig. 2), and therefore this

Conclusion

A natural product-based 2-aryl polyhydroxylated pyrrolidine alkaloid library with three diversity elements (one structural diversity; two substituent diversities) has been efficiently prepared using the chiral cyclic nitrones 4 and 5 as starting materials. Based on this solution-phase combinatorial approach, our small molecule library is obtained in high yield and purity and in excellent stereoselectivity. This synthetic protocol is expected to be suitable for a large library preparation with

Chemistry

Mass spectra were measured with a Bruker BioTOF III (ESI-MS). Optical rotations were measured with a PerkinElmer Model 341 polarimeter. NMR spectra (1H at 400 or 600 MHz, 13C at 100 or 150 MHz) were recorded in CDCl3, CD3OD, or D2O solvents. Silica gel was used Merck Kieselgel Si60 (40–63 μm) and CC refers to column chromatography. Thin layer chromatography (TLC) was performed on glass plates coated to a thickness of 1 mm with Merck Kieselgel 60F254. All reagents, enzymes, substrates, and solvents

Acknowledgment

This work was supported by the National Science Council and Academia Sinica.

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