Bioorganic & medicinal chemistry

Cytotoxicity and topoisomerase I/II inhibition of glycosylated 2-phenyl-indoles, 2-phenyl-benzo[b]thiophenes and 2-phenyl-benzo[b]furans.

PMID 21094049


A panel of glycosylated DNA binding agents (1-12) designed as functional anthracycline mimics was screened against three solid-tumor cell lines (MCF-7, HT 29 and HepG2/C3A) and three non-tumor cell lines by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability assay. Several compounds showed better in vitro cytotoxicity and selectivity against MCF-7 cells than daunomycin and doxorubicin, two known DNA binding agents that are clinically-used anti-cancer agents. Although the selectivity for HT 29 and HepG2/C3A cells is generally lower, the IC(50) values of some analogs against these two cancer cell lines were of the same magnitude as doxorubicin. Because there was no correlation between DNA binding affinity and cytotoxicity, and because topoisomerase (Topo) inhibition is another biological mechanism of action of most anthracycline drugs, Topo I/II inhibition assays with 1-12 were performed. Some of the compounds showed strong inhibition against these enzymes at 100μM, but there was no clear correlation between cytotoxicity and Topo I/II inhibition ability. Topo I/II inhibition mode assays were also performed, which verified that these compounds are topoisomerase suppressors, not poisons. Based on these results, we conclude that although DNA binding and/or topoisomerase inhibition may contribute to the observed cytotoxicity of 1-12, other mechanisms of action are also likely to be important.