| Abstract
| - A set of 10 compounds, each combining the seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (seco-CBI) and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) pharmacophores, was designedand prepared. These compounds were anticipated to cross-link between N3 of adenine and N2of guanine in the minor groove of DNA. The compounds, which differ in the chain lengthseparating the two alkylation subunits, and the configuration of the CBI portion, showed greatvariation in cellular toxicity (over 4 orders of magnitude in a cell line panel) with the mostpotent example exhibiting IC50s in the pM range. Cytotoxicity correlated with the ability ofthe compounds to cross-link naked DNA. Cross-linking was also observed in living cells, atmuch lower concentrations than for a related symmetrical PBD dimer. A thermal cleavageassay was used to assess sequence selectivity, demonstrating that the CBI portion controlledthe alkylation sites, while the PBD substituent increased the overall efficiency of alkylation.Several compounds were tested for in vivo activity using a tumor growth delay assay againstWiDr human colon carcinoma xenografts, with one compound (the most cytotoxic and mostefficient cross-linker) showing a statistically significant increase in survival time following asingle iv dose.
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