PMID: 11606127Oct 19, 2001Paper

Synthesis of sulfaphenazole derivatives and their use as inhibitors and tools for comparing the active sites of human liver cytochromes P450 of the 2C subfamily

Journal of Medicinal Chemistry
N T Ha-DuongD Mansuy

Abstract

Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH(2) and H (of the SO(2)NH function) substituents of SPA with various R(1) and R(2) groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC(50) < 1 microM) were only observed for SPA derivatives having the SO(2)NH function and a relatively small R(1) substituent (R(1) = NH(2), CH(3)). Any increase in the size of R(1) led to a moderate decrease of the affinity, and the N-alkylation of the SO(2)NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R(1) and R(2) substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 show...Continue Reading

References

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Citations

Oct 26, 2007·Journal of Computer-aided Molecular Design·Tímea PolgárGyörgy M Keseru
Nov 19, 2003·Archives of Biochemistry and Biophysics·Sandra L PfisterWilliam B Campbell
Apr 10, 2004·Drug Metabolism Reviews·Corwin HanschRajeshwar Prasad Verma
Dec 30, 2015·PLoS Neglected Tropical Diseases·Peter D ZinielDavid L Williams
Nov 1, 2013·Chemistry : a European Journal·Johannes SchranckMatthias Beller
Feb 16, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·R S FotiJ G Slatter
Sep 9, 2004·Chemical Reviews·Bernard MeunierSason Shaik

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