Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs

• Published in: Bioorganic & medicinal chemistry 2014-01, Vol.22 (1), p.211-220
• Main Authors: Ashour, Ahmed, El-Sharkawy, Saleh, Amer, Mohamed, Abdel Bar, Fatma, Katakura, Yoshinori, Miyamoto, Tomofumi, Toyota, Nozomi, Bang, Tran Hai, Kondo, Ryuichiro, Shimizu, Kuniyoshi
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Humans; Inhibitor; Models, Molecular; Oleanolic acid; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - metabolism; SARS; Topoisomerase I and II; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.11.034

Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12–C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα.