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.

6'-Hydroxy-3'-methoxy-mitorubrin, a New Potentiator of Antifungal Miconazole Activity, Produced by Penicillium radicum FKI-3765-2

“…The IR absorption at 1450 cm Ϫ1 , 1625-1712 cm Ϫ1 and 3426 cm Ϫ1 suggested the presence of phenyl, carbonyl and hydroxy groups in the structure. These data were similar to those of 2 and 3, 15,16) suggesting that 1 also has a common isochromane-like ring with a similar hydrophobic side chain.…”

“…GGTase I was reported to be responsible for cell wall biosynthesis of C. albicans. 15) Therefore, it might be that mitorubrins inhibit GGTase I to potentiate miconazole activity, but it remains to be defined. Regarding antimicrobial activity against other microorganisms, as described in Experimental, these compounds showed very weak antibacterial activity only against X. camperstris with the same size (7 mm) of inhibition zone at 10 mg/6 mm disk, but no activity against the other five microorganisms.…”

“…Biological Properties Compound 2 was reported as a geranylgeranyltransferase I (GGTase I) inhibitor, 15) while the biological activity of 3 has not been reported. In this study, they were found to have miconazole-potentiating activity against C. albicans.…”

“…From precise analysis of the metabolites of xanthoradone-producing Penicillium radicum FKI-3765-2, 13) a new compound, designated 6Ј-hydroxy-3Ј-methoxy-mitorubrin (1, Fig. 1), with a core structure different from that of xanthoradones 14) was isolated along with known 4Ј-hydroxy-3Ј-methoxy-(S)-mitorubrin 15) (2) and monomethyl-(S)-mitorubrin 16) (3). In this study, fermentation, isolation, and structural elucidation, including the absolute stereochemistry and miconazole-potentiating activity, of 1 are described.…”

The Chemical Constituents of Endophytic Fungus Trichoderma sp. MFF‐1

“…Mitorubrin and derivatives display diverse biological activities [16] [17]. Compounds 1 and 2 were tested for in vitro cytotoxicity against HL-60, SK-BR-3, PANC-1, A549, and SMMC-7721 cell lines by means of the MTT ( ¼ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) method, but did not show obvious activities at 40 mm.…”