- Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors
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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 IIR 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.
- Abdel Bar, Fatma M.,Khanfar, Mohammad A.,Elnagar, Ahmed Y.,Liu, Hui,Zaghloul, Ahmed M.,Badria, Farid A.,Sylvester, Paul W.,Ahmad, Kadria F.,Raisch, Kevin P.,El Sayed, Khalid A.
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experimental part
p. 1643 - 1650
(2010/03/31)
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