Novel leptomycins from a streptomyces strain A92‐308902: Inhibitors of the Nucleo‐cytoplasmic translocation of the HIV‐1 regulatory protein Rev

As one of the regulatory gene products in the HIV-1 genome, Rev protein 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 strain A92-308902 with very potent inhibitory activity was found in the course of a high throughput screening with a Rev translocation assay (RTA). Bioassay-guided fractionation with gel filtration, normal-phase and reversed-phase chromatography yielded six RTA-active metabolites belonging to the leptomycin family, the known leptomycin A (1), leptomycin B (2), kazusamycin B (3), and kazusamycin A (4). and the hitherto unknown dilactonmycin (5) and delactonmycin (6), together with an inactive cyclic hexadepsipeptide L-156,620 (7). The structures were established mainly by spectroscopic methods (UV, FT-IR, FAB-MS, 1H-NMR, 13C-NMR(JMOD), DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all CC bonds of 1–6 was unambiguously established by analysis of coupling constants and ROESY spectra. All isolated leptomycins 1–6 inhibit Rev translocation at nanomolar concentrations. Six derivatives (2a–c and 4a–c) of leptomycin B (2) and kazusamycin A (4) were also prepared and tested in the RTA for preliminary investigations on structure-activity relationships.