PYRROLO[1,2-A]BENZIMIDAZOLE-BASED QUINONES AND IMINOQUINONES - THE ROLE OF THE 3-SUBSTITUENT ON CYTOTOXICITY

The influence of the 3-substituent on the cytotoxicity of the 6-azirid inylpyrrolo[1,2-a]benzimidazole quinones (PBIs), the 6-acetamidopyrrol o[1,2-a]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2 -a]benzimidazole iminoquinones (imino-APBIs) was investigated by compa ring LC(50) mean graphs consisting of 60 cancer lines. Increasing lipo philicity of the 3-substituent of PBIs and APBIs increased the cytotox icity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the S-carbamate der ivative which shows enhanced cleavage. This property of the 3-carbamat e is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer ce ll lines; the correlation coefficient for log LC(50) VS log lipophilic ity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are act ivated by DT-diaphorase but that the APBIs and imino-APBIs are inactiv ated by this enzyme. Thus the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanisti c similarities between both types of cytotoxic agents. Major conclusio ns of this study pertain to the design of agents displaying cytotoxici ty specifically against melanoma and renal cancers and to the use of 6 0-cell line mean graphs and COMPARE in cancer drug QSAR.