Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors

  • J Nat Prod. 2009 Sep;72(9):1643-50. doi: 10.1021/np900312u.
Fatma M Abdel Bar  1 ,  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
Affiliations
  • 1. Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
PMID: 19691293 DOI: 10.1021/np900312u
Abstract

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 IIalpha 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-17beta-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 IIalpha inhibitors.