Rational Design and Semisynthesis of Betulinic Acid Analogues as Potent Topoisomerase Inhibitors
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- 作者：Fatma M. Abdel Bar ; Mohammad A. Khanfar ; Ahmed Y. Elnagar ; Hui Liu ; Ahmed M. Zaghloul ; Farid A. Badria ; Paul W. Sylvester ; Kadria F. Ahmad ; Kevin P. Raisch ; Khalid A. El Sayed
- 刊名：Journal of Natural Products
- 出版年：2009
- 出版时间：September 25, 2009
- 年：2009
- 卷：72
- 期：9
- 页码：1643-1650
- 全文大小：280K
- 年卷期：v.72,no.9(September 25, 2009)
- ISSN：1520-6025
文摘
Chemical transformation studies were conducted on betulinic acid (1), a common plant-derived lupane-type triterpene. Eleven new rationally designed derivatives of 1 (2−5 and 7−13) were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-20, and C-28 in 1. Structures of the new compounds were confirmed by spectroscopic methods (1D and 2D NMR and MS). Compound 9, 3-O-[N-(phenylsulfonyl)carbamoyl-17β-N-(phenylsulfonyl)amide]betulinic acid, showed 1.5-fold the activity of CPT in a topoisomerase I DNA relaxation assay. Four out of 14 betulinic acid analogues (5, 9, 11, and 12) showed 1.5-fold the activity of etoposide in a topoisomerase II assay. The new analogues exhibited better cytotoxic activities against the human colon cancer cells SW948 and HCT-116 and the breast cancer cell line MDA-MB-231 compared to the parent (1). Betulinic acid (1) is a potential scaffold for the design of new topoisomerase I and IIα inhibitors.