An efficient synthesis and the cytotoxic activity of a series of substituted 6-amino-4H-[1,2]dithiolo[4,3-b]pyrrol-5-ones 1a-q is described. The synthesis was accomplished in an expedient manner (seven-steps) from commercially available starting materials. Several of the derivatives tested demonstrated significant in vitro cytotoxic activity against the human cancer cell lines H460 (7nM) and LCC6 (> or =28nM). Following SAR and pharmacokinetic studies a derivative was further evaluated for its in vivo anti-tumor activity against a highly angiogenic human melanoma xenograft where it demonstrated significant efficacy as a mono-therapy and in combination with Taxol and Cisplatin.