Potent and selective inhibition of human cytochrome P450 3A4 by seco-pancratistatin structural analogs.
seco-Derivatives of the anticancer agent pancratistatin bearing the 2S,3S,4S,5S configuration were accessed via a novel, highly diastereoselective anti-aldol reaction. Structure-activity relationships reveal important insights into the seco-pancratistatin pharmacophore as a potent and selective inhibitor of human cytochrome P450 3A4 (CYP3A4), and highlight features of concern in advancing a potent, selective anticancer agent in the pancratistatin series.
McNulty
James
J
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4M1. jmcnult@mcmaster.ca
Nair
Jerald J
JJ
Singh
Mohini
M
Crankshaw
Denis J
DJ
Holloway
Alison C
AC
D047151:Amaryllidaceae Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D019668:Liliaceae / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D047151:Amaryllidaceae Alkaloids; D065692:Cytochrome P-450 CYP3A Inhibitors; D007546:Isoquinolines; C044997:pancratistatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human