title: Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs.
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.
authors: Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors: Ahmed
authors: A
authors: Ashour
authors: Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Department of Pharmacognosy, Faculty of Pharmacy, Delta University for Science and Technology, Egypt.
authors: Saleh
authors: S
authors: El-Sharkawy
authors: Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors: Mohamed
authors: M
authors: Amer
authors: Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors: Fatma
authors: F
authors: Abdel Bar
authors: Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
authors: Yoshinori
authors: Y
authors: Katakura
authors: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors: Tomofumi
authors: T
authors: Miyamoto
authors: Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
authors: Nozomi
authors: N
authors: Toyota
authors: Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
authors: Tran Hai
authors: TH
authors: Bang
authors: Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
authors: Ryuichiro
authors: R
authors: Kondo
authors: Department of Agro-Environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, Japan. Electronic address: shimizu@agr.kyushu-u.ac.jp.
authors: Kuniyoshi
authors: K
authors: Shimizu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C413246:oleanane; D009828:Oleanolic Acid
keywords: Inhibitor; Oleanolic acid; SARS; Topoisomerase I and II