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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemistry
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Alkaloids / isolation & purification*
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Alkaloids / pharmacology*
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Amaryllidaceae Alkaloids / chemistry
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Amaryllidaceae Alkaloids / isolation & purification*
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Amaryllidaceae Alkaloids / pharmacology*
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / isolation & purification*
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Antineoplastic Agents, Phytogenic / pharmacology*
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Crystallography, X-Ray
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Cytochrome P-450 CYP1A1 / antagonists & inhibitors*
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors*
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Drug Screening Assays, Antitumor
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Humans
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Molecular Structure
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Narcissus / chemistry*
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Phenanthridines / chemistry
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Phenanthridines / isolation & purification*
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Phenanthridines / pharmacology*
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Stereoisomerism
Substances
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Alkaloids
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Amaryllidaceae Alkaloids
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Antineoplastic Agents, Phytogenic
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Cytochrome P-450 CYP3A Inhibitors
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Phenanthridines
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narciclasine
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dihydronarciclasine
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human