Synthesis and antiproliferative activity of (5R)-cleistenolide and analogues

• Published in: Journal of the Serbian Chemical Society Vol. 88; no. 7-8; pp. 705 - 713
• Main Authors: Farkas, Sándor, Benedekovic, Goran, Stanisavljevic, Sladjana, Sreco-Zelenovic, Bojana, Popsavin, Mirjana, Popsavin, Velimir, Jakimov, Dimitar
• Format: Journal Article
• Language: English
• Published: Serbian Chemical Society 2023
• Subjects: (5r)-cleistenolide; antitumour agents; intramolecular mitsunobu reaction; sar analysis; sugar δ-lactones; z-selective wittig olefination
• ISSN: 0352-5139; 1820-7421
• DOI: 10.2298/JSC230126018F

(5R)-Cleistenolide and a few related analogues have been synthesized starting from d-glucose. The key steps of the synthesis included a Z-selective Wittig olefination and an intramolecular Mitsunobu reaction with an inversion of configuration at the C-5 position. In vitro antiproliferative activity of synthesized compounds was tested on a panel of eight human tumour cells and against a single normal cell line (MRC-5). The majority of tested compounds showed strong antiproliferative effects on certain human tumour cells and all of them showed negligible toxicity to normal foetal lung fibroblasts (MRC-5). The most active compound obtained in this work is lactone 5, which in MDA-MB 231 cell culture showed the same activity as doxorubicin (IC50 0.09 ?M). Strong antiproliferative activities of analogues 2, 5 and 6 were recorded in the K562 cell line (IC50 0.21, 0.34 and 0.33 ?M, respectively), in which they showed very similar activities to doxorubicin (IC50 0.25 ?M). A performed SAR study revealed that a change in the stereochemistry at the C-5 position may increase the activity of resulting stereoisomers.