Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors.
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.
Bar
Fatma M Abdel
FM
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Khanfar
Mohammad A
MA
Elnagar
Ahmed Y
AY
Liu
Hui
H
Zaghloul
Ahmed M
AM
Badria
Farid A
FA
Sylvester
Paul W
PW
Ahmad
Kadria F
KF
Raisch
Kevin P
KP
El Sayed
Khalid A
KA
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
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