Potent and selective inhibition of human cytochrome P450 3A4 by seco-pancratistatin structural analogs

James McNulty; Jerald J Nair; Mohini Singh; Denis J Crankshaw; Alison C Holloway

doi:10.1016/j.bmcl.2010.01.157

Potent and selective inhibition of human cytochrome P450 3A4 by seco-pancratistatin structural analogs

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2335-9. doi: 10.1016/j.bmcl.2010.01.157. Epub 2010 Feb 4.

Authors

James McNulty¹, Jerald J Nair, Mohini Singh, Denis J Crankshaw, Alison C Holloway

Affiliation

¹ Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4M1. jmcnult@mcmaster.ca

PMID: 20189386
DOI: 10.1016/j.bmcl.2010.01.157

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amaryllidaceae Alkaloids / chemistry*
Amaryllidaceae Alkaloids / pharmacology*
Cytochrome P-450 CYP3A / pharmacology*
Cytochrome P-450 CYP3A Inhibitors*
Humans
Isoquinolines / chemistry*
Isoquinolines / pharmacology*
Liliaceae / chemistry
Models, Molecular
Structure-Activity Relationship

Substances

Amaryllidaceae Alkaloids
Cytochrome P-450 CYP3A Inhibitors
Isoquinolines
pancratistatin
Cytochrome P-450 CYP3A
CYP3A4 protein, human