Antitumor agents. 284. new desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents

We previously reported that the biological acti-vity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI₅₀ values of 0.8-2.1 μM. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistant cell line. We have now prepared and evaluated 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI₅₀ values of 0.06-0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC₅₀ value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.