Desmosdumotin B (DesB, 1 ) has a unique flavonoid skeleton with an unusual non-aromatic trimethylated ring-A (Fig. 1 ). DesB (1 )and its triethylated analogs (TEDBs), including 2 and 3 , inhibited only P-gp overexpressing multidrug resistant (MDR) tumor cell growth, leading to significant nonMDR/MDR selectivity. Interestingly, analogs with a bicyclic aryl ring-B (TEDB-TB), such as benzothiophene 4 and naphthalene 5 , displayedadramaticallydifferentbioactivity profile, with potent cell growth inhibition against multiple cancer cell lines. These analogs inhibited tubulin polymerization, partially through the colchicine binding site. Importantly, none of the analogs were P-gp substrates, and thus, they were effective against MDR tumors. In structure-activity relationship studies of bicyclic ring-B analogs, various functional groups were installed on ring-B of 4 and 5 to provide better solubility. The newly synthesized analogs were evaluated for cytotoxicity, and their effects on microtubule dynamics. Regardless of the position or character of the functional group, all cytotoxic analogs inhibited the onset of metaphase. While clinically successful tubulin inhibitors target both the mitotic spindle and interphase microtubules in chemosensitive cancer cells, the new analogs effectively inhibited bipolar mitotic spindle formation without interfering with interphase microtubule dynamics in both chemosensitive and MDR cancer cells. Therefore, these TEDB analogs might be promising candidates leading to a new chemotherapeutic drug targeting tubulin, and offer the possibility of overcoming MDR obstacles and reducing unexpected effects in normal cells at interphase. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/239nm/uploads/1989_figure1.jpg' alt='' />

TEDB-TB analogs as new classes of tubulin inhibitors

246th National Meeting (2013)

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