Isolation and structure determination of streptospherins B-F, novel cancer stem cell inhibitors, produced by Streptomyces sp. KUSC-240.

Streptospherin A (1), which has pentasubstituted benzene and tetrahydropyran moieties, was recently isolated in our laboratory from Streptomyces sp. KUSC-240 as a novel inhibitor of cancer stem cell (CSC) sphere formation. Given the potential of CSCs as target for cancer therapy because of their high malignancy, identification of CSC inhibitors is urgently needed. The chemical structure and biological activity of 1 prompted us to isolate other derivatives from Streptomyces sp. KUSC-240, leading here to the identification of new streptospherins B-F (2-6). Their planar structures were determined by HR-ESI-MS and NMR analyses. The absolute configuration of 4 was proposed by using a modified Mosher's method, acetonide formation, and the J-based configuration analysis (JBCA) method. The absolute configurations of 3 and 5 were also determined by using ECD spectra and comparison with that of 4. Analysis of the whole genome sequence of the producing strain suggested a plausible biosynthesis pathway for 3-5. Compounds 2-6 inhibited CSC sphere formation and suppressed CSC growth, indicating that streptospherins are promising seed compounds for CSC inhibitors for cancer chemotherapy.