title: 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.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1. jmcnult@mcmaster.ca
authors.forename: James
authors.initials: J
authors.lastname: McNulty
authors.forename: Amol
authors.initials: A
authors.lastname: Thorat
authors.forename: Nesrin
authors.initials: N
authors.lastname: Vurgun
authors.forename: Jerald J
authors.initials: JJ
authors.lastname: Nair
authors.forename: Emilija
authors.initials: E
authors.lastname: Makaji
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Crankshaw
authors.forename: Alison C
authors.initials: AC
authors.lastname: Holloway
authors.forename: Siyaram
authors.initials: S
authors.lastname: Pandey
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D047151:Amaryllidaceae Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D031427:Narcissus / Q000737:chemistry*; D010617:Phenanthridines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D010617:Phenanthridines; C010753:narciclasine; C064338:dihydronarciclasine; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human