Structure-activity studies on seco-pancratistatin analogs: potent inhibitors of human cytochrome P450 3A4

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

doi:10.1016/j.bmcl.2009.08.032

Structure-activity studies on seco-pancratistatin analogs: potent inhibitors of human cytochrome P450 3A4

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5607-12. doi: 10.1016/j.bmcl.2009.08.032. Epub 2009 Aug 13.

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: 19713107
DOI: 10.1016/j.bmcl.2009.08.032

Abstract

Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are reported. Structure-activity relationship (SAR) studies identified potent and selective inhibitors of human cytochrome P450 3A4 (CYP3A4) and revealed several core pharmacophoric elements. These studies identify potential roadblocks and will guide the further development of a viable selective clinical pancratistatin derivative.

Publication types

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

MeSH terms

Amaryllidaceae Alkaloids / chemical synthesis
Amaryllidaceae Alkaloids / chemistry*
Amaryllidaceae Alkaloids / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors*
Humans
Isoquinolines / chemical synthesis
Isoquinolines / chemistry*
Isoquinolines / pharmacology
Structure-Activity Relationship

Substances

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