title: New fungal metabolite geranylgeranyltransferase inhibitors with antifungal activity.
abstract: Geranylgeranyltransferase I (GGTase I) catalyzes the post-translational transfer of lyophilic diterpenoid geranylgeranyl to the cysteine residue of proteins terminating with a CaaX motif such as Rho1p and Cdc42p. It has been shown that GGTase I activity is essential for viability of Saccharomyces cerevisiae and hence its inhibition is a potential antifungal target. From natural product screening, a number of azaphilones including one novel analog were isolated as broad-spectrum inhibitors of GGTase I. Isolation, structure elucidation, GGTase I inhibitory activities and antifungal activities of these compounds are described.
authors.affiliation: Merck Research laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. sheo_singh@merck.com
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Kelly
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: Anne W
authors.initials: AW
authors.lastname: Domrowski
authors.forename: Javier
authors.initials: J
authors.lastname: Collado
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Fernando
authors.initials: F
authors.lastname: Pelaez
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Register
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Kelly
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bonfiglio
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Williamson
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010860:Pigments, Biological / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors
chemical_list: D000935:Antifungal Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D010860:Pigments, Biological; D029701:Saccharomyces cerevisiae Proteins; C494154:azaphilone; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I