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

Ahmed Ashour, Saleh El-Sharkawy, Mohamed Amer, Fatma Abdel Bar, Yoshinori Katakura, Tomofumi Miyamoto, Nozomi Toyota, Tran Hai Bang, Ryuichiro Kondo, Kuniyoshi Shimizu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)211-220
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Topoisomerase II Inhibitors
Oleanolic Acid
Pharmaceutical Preparations
Neoplasms
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Assays
ethyl-2-methylthio-4-methyl-5-pyrimidine carboxylate
Topoisomerase I Inhibitors
S 6
Camptothecin
Etoposide
Skeleton
Nuclear magnetic resonance
Derivatives

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Rational design and synthesis of topoisomerase i and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs. / Ashour, Ahmed; El-Sharkawy, Saleh; Amer, Mohamed; Abdel Bar, Fatma; Katakura, Yoshinori; Miyamoto, Tomofumi; Toyota, Nozomi; Bang, Tran Hai; Kondo, Ryuichiro; Shimizu, Kuniyoshi.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 1, 01.01.2014, p. 211-220.

Research output: Contribution to journalArticle

Ashour, Ahmed ; El-Sharkawy, Saleh ; Amer, Mohamed ; Abdel Bar, Fatma ; Katakura, Yoshinori ; Miyamoto, Tomofumi ; Toyota, Nozomi ; Bang, Tran Hai ; Kondo, Ryuichiro ; Shimizu, Kuniyoshi. / Rational design and synthesis of topoisomerase i and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 1. pp. 211-220.
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