title: Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors.
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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
authors.forename: Fatma M Abdel
authors.initials: FM
authors.lastname: Bar
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Khanfar
authors.forename: Ahmed Y
authors.initials: AY
authors.lastname: Elnagar
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Zaghloul
authors.forename: Farid A
authors.initials: FA
authors.lastname: Badria
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: Kadria F
authors.initials: KF
authors.lastname: Ahmad
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Raisch
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D004247:DNA / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D053978:Pentacyclic Triterpenes; D059004:Topoisomerase I Inhibitors; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: C544233:3-O-(N-(phenylsulfonyl)carbamoyl-17beta-N-(phenylsulfonyl)amide)betulinic acid; D053978:Pentacyclic Triterpenes; D059004:Topoisomerase I Inhibitors; D014315:Triterpenes; D004247:DNA; D000094062:Betulinic Acid