Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoformsElectronic supplementary information (ESI) available: General chemical methods; natural products & synthetic chemistry; isothermal titration calorimetry data; in vitro HUVEC anti-angiogenesis assays; RPE cell culture and VEGF experiments; correction of the FBP21 cDNA expression vector. See DOI: 10.1039/c0sc00297f

The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning of a phage display library of colon tumour cell cDNAs identified the tandem WW domains of spliceosome-associated protein formin binding protein 21 (FBP21) as a novel molecular target of borrelidin, suggesting that borrelidin may act as a modulator of alternative splicing. In support of this idea, 1 , and its more selective analog 2 , bound to purified recombinant WW domains of FBP21. They also altered the ratio of vascular endothelial growth factor (VEGF) isoforms in retinal pigmented endothelial (RPE) cells in favour of anti -angiogenic isoforms. Transfection of RPE cells with FBP21 altered the ratio in favour of pro-angiogenic VEGF isoforms, an effect inhibited by 2 . These data implicate FBP21 in the regulation of alternative splicing and suggest the potential of borrelidin analogs as tools to deconvolute key steps of spliceosome function. FBP21 was identified as a molecular target of borrelidin by affinity methods & borrelidin and analogs modulate VEGF alternative splicing.