PMID: 8109933Dec 1, 1993

Ro 09-1470 is a selective inhibitor of P-450 lanosterol C-14 demethylase of fungi

Antimicrobial Agents and Chemotherapy
Y AokiM Arisawa

Abstract

Ro 09-1470 is a new antifungal agent that belongs to a series of compounds characterized by a tetrahydropyran skeleton with glycine and alkenyl side chains and that inhibits P-450 lanosterol C-14 demethylase (P-450(14DM)) of fungi (Y. Aoki, T. Yamazaki, M. Kondoh, Y. Sudoh, N. Nakayama, Y. Sekine, H. Shimada, and M. Arisawa, J. Antibiot. 45:160-170, 1992; S. Matsukuma, T. Ohtsuka, H. Kotaki, H. Sawairi, T. Sano, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yokose, and T. Okuda, J. Antibiot. 45:151-159, 1992). We have studied the compound's mode of interaction with fungal P-450(14DM) and its selectivity for the fungal versus mammalian P-450 enzymes. Ro 09-1470 bound to the Saccharomyces cerevisiae P-450(14DM) by coordinating to the heme with one-to-one stoichiometry. Unlike the azole compounds, it interacted with both ferric and ferrous heme. It was active also against the P-450(14DM) of Candida albicans. Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 microM), p-nitroanisol O-demethylation (> 1,000 microM), aniline...Continue Reading

References

Jan 1, 1992·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·P Soucek, I Gut
May 31, 1991·Biochemical and Biophysical Research Communications·J L RaucyJ M Trzaskos
Mar 1, 1990·Antimicrobial Agents and Chemotherapy·K L LavrijsenJ J Heykants
Nov 1, 1987·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A D RodriguesD V Parke
Jul 1, 1986·Biochemical Pharmacology·D F LewisD V Parke
Nov 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·J RineR W Davis

Related Concepts

Ro 09-1470
Cyp51 protein, rat
Metazoa
Antibiotics, Antifungal
Carbon Monoxide
Epicholesterol
Cytochrome P-450 Oxygenase
Yeast Proteins
Glycine, Monopotasssium Salt
Heme

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