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Bioorg Med Chem. 2014 Jan 1;22(1):211-20. doi: 10.1016/j.bmc.2013.11.034. Epub 2013 Nov 25.

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

Author information

  • 1Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 2Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Department of Pharmacognosy, Faculty of Pharmacy, Delta University for Science and Technology, Egypt.
  • 3Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 4Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
  • 5Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • 6Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
  • 7Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan. Electronic address: shimizu@agr.kyushu-u.ac.jp.

Abstract

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Inhibitor; Oleanolic acid; SARS; Topoisomerase I and II

PMID:
24326278
[PubMed - indexed for MEDLINE]
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