NOVEL LEPTOMYCINS FROM A STREPTOMYCES STRAIN A92-308902 - INHIBITORS OF THE NUCLEOCYTOPLASMIC TRANSLOCATION OF THE HIV-1 REGULATORY PROTEINREV

As one of the regulatory gene products in the HIV-1 genome, Rev protei n must be translocated from the nucleus to the cytoplasm to exert its function. Therefore, inhibition of Rev protein translocation could be a useful target for HIV therapy. An extract from the Streptomyces stra in A92-308902 with very potent inhibitory activity was found in the co urse of a high throughput screening with a Rev translocation assay (RT A). Bioassay-guided fractionation with gel filtration, normal-phase an d reversed-phase chromatography yielded six RTA-active metabolites bel onging to the leptomycin family, the known leptomycin A (1), leptomyci n B (2), kazusamycin B (3), and kazusamycin A (4), and the hitherto un known dilactonmycin (5) and delactonmycin (6), together with an inacti ve cyclic hexadepsipeptide L-156,620 (7). The structures were establis hed mainly by spectroscopic methods (UV, FT-IR, FAB-MS,H-1-NMR,C-13-NM R(JMOD),DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all C = C bonds of 1-6 was unambiguously established by analysis of coupling c onstants and ROESY spectra. All isolated leptomycins 1-6 inhibit Rev t ranslocation at nanomolar concentrations. Six derivatives (2a-c and 4a -c) of leptomycin B (2) and kazusamycin A (4) were also prepared and t ested in the RTA for preliminary investigations on structure-activity relationships.