Potent spliceostatin analogs isolated from Pseudomonas by mixed fermentation and modifications of culture conditions

Recently, the SF3b subunit of the spliceosome was identified as a target for the natural products pladienolide, herboxidiene and spliceostatin A. These metabolites show in-vitro activity in tumor cell lines with IC₅₀ values in the low nanomolar range, induce cell cycle arrest at the G1 and G2/M phases and block angiogenesis. Spliceostatin analogs have been reported from Pseudomonas sp. and Burkholderia sp. Several reports suggest that the epoxide group of spliceostatin A is indispensable for the antitumor activity. However, by co-culturing Pseudomonas with other bacteria as well as varying fermentation time and media composition, we were able to isolate several new analogs of spliceostatin A without the epoxide functionality. Notably, some of these metabolites exhibit GI₅₀ values between <0.1 nM –25 nM on the NCI60 Tumor Cell Line screen. In addition to analyze the SAR, we also explored the biosynthetic origin of these novel inhibitors in order to understand and improve their production. Funded by NCI Contract No. HHSN261200800001E.