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Cytochrome P450 3A4 inhibitory activity studies within the lycorine series of alkaloids. 2010

James McNulty, and Jerald J Nair, and Mohini Singh, and Denis J Crankshaw, and Alison C Holloway, and Jaume Bastida
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. jmcnult@mcmaster.ca

A mini-panel of semi-synthetic analogs of the Amaryllidaceae alkaloid lycorine was screened for cytochrome P450 3A4 (CYP3A4) inhibitory activity, the most potent of which exhibited inhibition as low as 0.21 microM. Elements of this novel pharmacophore unravelled include bulky lipophilic substitution at C2 in conjunction with a small hydrogen bond donor/acceptor at C1, or bulky electron-rich substitution at C1 in conjunction with a vicinal hydrogen bond donor/acceptor.

UI MeSH Term Description Entries
D010617 Phenanthridines
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047151 Amaryllidaceae Alkaloids Alkaloids derived from TYRAMINE combined with 3,4-dihydroxybenzaldehyde via a norbelladine pathway, including GALANTAMINE, lycorine and crinine. They are found in the AMARYLLIDACEAE plant family. Benzazepine-Type Amaryllidaceae Alkaloids,Galanthamine-Type Amaryllidaceae Alkaloids,Norbelladine-Type Amaryllidaceae Alkaloids,Alkaloids, Amaryllidaceae,Amaryllidaceae Alkaloids, Benzazepine-Type,Amaryllidaceae Alkaloids, Galanthamine-Type,Amaryllidaceae Alkaloids, Norbelladine-Type,Benzazepine Type Amaryllidaceae Alkaloids,Galanthamine Type Amaryllidaceae Alkaloids,Norbelladine Type Amaryllidaceae Alkaloids
D051544 Cytochrome P-450 CYP3A A cytochrome P-450 suptype that has specificity for a broad variety of lipophilic compounds, including STEROIDS; FATTY ACIDS; and XENOBIOTICS. This enzyme has clinical significance due to its ability to metabolize a diverse array of clinically important drugs such as CYCLOSPORINE; VERAPAMIL; and MIDAZOLAM. This enzyme also catalyzes the N-demethylation of ERYTHROMYCIN. CYP3A,CYP3A4,CYP3A5,Cytochrome P-450 CYP3A4,Cytochrome P-450 CYP3A5,Cytochrome P-450IIIA,Cytochrome P450 3A,Cytochrome P450 3A4,Cytochrome P450 3A5,Erythromycin N-Demethylase,Taurochenodeoxycholate 6-alpha-Monooxygenase,3A5, Cytochrome P450,6-alpha-Monooxygenase, Taurochenodeoxycholate,Cytochrome P 450 CYP3A,Cytochrome P 450 CYP3A4,Cytochrome P 450 CYP3A5,Cytochrome P 450IIIA,Erythromycin N Demethylase,N-Demethylase, Erythromycin,P-450 CYP3A, Cytochrome,P-450 CYP3A4, Cytochrome,P-450 CYP3A5, Cytochrome,P-450IIIA, Cytochrome,P450 3A, Cytochrome,P450 3A5, Cytochrome,Taurochenodeoxycholate 6 alpha Monooxygenase
D065692 Cytochrome P-450 CYP3A Inhibitors Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A. CYP3A Inhibitor,CYP3A5 Inhibitor,CYP3A7 Inhibitor,Cyp3A4 Inhibitor,Cytochrome P-450 CYP3A Inhibitor,Cytochrome P-450 CYP3A4 Inhibitor,Cytochrome P-450 CYP3A5 Inhibitor,Cytochrome P-450 CYP3A7 Inhibitor,P450 CYP3A Inhibitor,P450 CYP3A4 Inhibitor,P450 CYP3A5 Inhibitor,P450 CYP3A7 Inhibitor,CYP3A Inhibitors,CYP3A4 Inhibitors,CYP3A5 Inhibitors,CYP3A7 Inhibitors,Cytochrome P-450 CYP3A4 Inhibitors,Cytochrome P-450 CYP3A5 Inhibitors,Cytochrome P-450 CYP3A7 Inhibitors,P450 CYP3A Inhibitors,P450 CYP3A4 Inhibitors,P450 CYP3A5 Inhibitors,P450 CYP3A7 Inhibitors,CYP3A Inhibitor, P450,CYP3A4 Inhibitor, P450,CYP3A5 Inhibitor, P450,CYP3A5 Inhibitors, P450,CYP3A7 Inhibitor, P450,CYP3A7 Inhibitors, P450,Cytochrome P 450 CYP3A Inhibitor,Cytochrome P 450 CYP3A Inhibitors,Cytochrome P 450 CYP3A4 Inhibitor,Cytochrome P 450 CYP3A4 Inhibitors,Cytochrome P 450 CYP3A5 Inhibitor,Cytochrome P 450 CYP3A5 Inhibitors,Cytochrome P 450 CYP3A7 Inhibitor,Cytochrome P 450 CYP3A7 Inhibitors,Inhibitor, CYP3A,Inhibitor, CYP3A5,Inhibitor, CYP3A7,Inhibitor, Cyp3A4,Inhibitor, P450 CYP3A,Inhibitor, P450 CYP3A4,Inhibitor, P450 CYP3A5,Inhibitor, P450 CYP3A7,Inhibitors, CYP3A,Inhibitors, CYP3A4,Inhibitors, CYP3A5,Inhibitors, CYP3A7,Inhibitors, P450 CYP3A,Inhibitors, P450 CYP3A4,Inhibitors, P450 CYP3A7

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