Synthesis of MeON-Glycoside Derivatives of Oleanolic Acid by Neoglycosylation and Evaluation of Their Cytotoxicity Against Selected Cancer Cell Lines.

Zhichao Du,Xiaoyang Zhou,Jian Zhang,Guolong Li

doi:10.3390/molecules26030772

Zhichao Du, Xiaoyang Zhou + Show 2 more

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https://doi.org/10.3390/molecules26030772

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Abstract

A series of C-3 and C-28 MeON-neoglycosides of oleanolic acid were designed and synthesized by neoglycosylation as potential antiproliferative agents. Their cytotoxicity was evaluated in vitro against five human cancer cell lines: human non-small cell lung cancer cell line (A549), human melanoma cell line (A375), human colon cancer cell line (HCT116), human liver carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) by the Cell Counting Kit-8 (CCK-8) assay. Most of C-3 and C-28 MeON-neoglycosides of oleanolic acid exhibited notably inhibitory effects against the tested cancer cells and more sensitive to HepG2 cells than 5-Fluorouracil (5-FU). Structure-activities relationship (SAR) analysis revealed that sugar types and the d/l configuration of sugars would significantly affect their antiproliferative activities of neoglycosides. Among them, compound 8a (28-N-methoxyaminooleanane-β-d-glucoside) exhibited the most potent antiproliferative activities against HepG2 cells with IC50 values of 2.1 µM. Further pharmacological experiments revealed that compound 8a could cause morphological changes and cell cycle arrest at G0/G1 phase and induce apoptosis in HepG2 cells. These results suggested that neoglycosylation could provide a rapid strategy for the discovery of potential antiproliferative agents and their possible pharmacological mechanisms need more further research.

Highlights

Glycosylation is a naturally occurring process and many natural products derive their pharmacological properties such as target recognition, toxicity and even mechanism of action through this process [1,2]
Oleanolic acid was esterified at the C-3 hydroxyl group using chloroacetyl chloride in the presence of DMAP
When comparing the antiproliferative activities of compounds 4a/4b, 4h/4i, 4j/4k, 4l/4m and 4p/4q, we found that compounds with D-sugars (4a, 4h, 4j, 4p) showed more potent antiproliferative activities than correspond compounds with L-sugars (4b, 4i, 4k, 4q) except the xylose C-3 MeON-neoglycosides (Table 1)

Summary

Introduction

Glycosylation is a naturally occurring process and many natural products derive their pharmacological properties such as target recognition, toxicity and even mechanism of action through this process [1,2]. The “Warburg effect” as a cellular phenomenon in cancer cells of displaying high rates of aerobic glycolysis with overexpression of glucose transporters such as GLUT1, provides clinically validated targets for cancer treatment [4,5]. Based on these fundamental insights, the design of glycoconjugates as various anticancer drugs becomes one of the important strategies in oncology research [5].

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