Human cytochrome P450 liability studies of trans-dihydronarciclasine: a readily available, potent, and selective cancer cell growth inhibitor.

Abstract

The cytochrome P45O activities of the naturally occurring Amaryllidaceae alkaloid narciclasine (3), isolated from Narcissus pseudonarcissus, and synthetic derivative trans-dihydronarciclasine (5) are reported. While narciclasine was found to possess potent inhibitory activity to human CYP3A4, its dihydro analogue was inactive. This study revealed that the C1-C10b double bond is required for inhibition of this crucial metabolizing enzyme. Compound 5 also demonstrated no inhibition of the related human cytochromes CYP19 and CYP1A1. This study elevates the status of trans-dihydronarciclasine (5) as a highly privileged, readily available molecule, with potent and selective anticancer activity.

• Authors: James McNulty, Amol Thorat, Nesrin Vurgun, Jerald J Nair, Emilija Makaji, Denis J Crankshaw, Alison C Holloway, Siyaram Pandey
• Journal: Journal of natural products (J Nat Prod) Vol. 74 Issue 1 Pg. 106-8 (Jan 28 2011) ISSN: 1520-6025 [Electronic] United States
• PMID: 21105682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Amaryllidaceae Alkaloids
• Antineoplastic Agents, Phytogenic
• Cytochrome P-450 CYP3A Inhibitors
• Phenanthridines
• narciclasine
• dihydronarciclasine
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• Alkaloids (chemistry, isolation & purification, pharmacology)
• Amaryllidaceae Alkaloids (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Crystallography, X-Ray
• Cytochrome P-450 CYP1A1 (antagonists & inhibitors)
• Cytochrome P-450 CYP3A
• Cytochrome P-450 CYP3A Inhibitors
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Narcissus (chemistry)
• Phenanthridines (chemistry, isolation & purification, pharmacology)
• Stereoisomerism