Geldanamycin

Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 μM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.

The molecular chaperone heat shock protein 90 (Hsp90) is highly conserved in eukaryotes and facilitates the correct folding, productive assembly and maturation of a diverse cellular proteins. In fungi, especially the most prevalent human fungal pathogen Candida albicans, Hsp90 influences development and modulates drug resistance. Here, we mainly explore the effect of non-Geldanamycin Hsp90 inhibitor HSP990 on the activity of fluconazole (FLC) against Candida albicans and investigate the underlying mechanism. We demonstrate that HSP990 has potent synergistic antifungal activity with FLC against FLC-resistant C. albicans through the checkerboard microdilution assay,agar diffusion tests and time-kill curves, and shows low cytotoxicity to human umbilical vein endothelial cells. Further study shows that the activity of FLC against C. albicans biofilm formation in vitro is significantly enhanced when used in combination with HSP990. In a murine model of disseminated candidiasis, the therapeutic efficacy of FLC is also enhanced by the pharmacological inhibition of C.