Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the 3-substituent on the cytotoxicity of the 6-aziridinylpyrrolo[1,2-a]-benzimidazole quinones (PBIs), the 6-acetamidopyrrolo[1,2-alpha]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2-alpha]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC50 mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the 3-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC50 vs log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated 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 mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR.
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PMID:Pyrrolo[1,2-a]benzimidazole-based quinones and iminoquinones. The role of the 3-substituent on cytotoxicity. 783 21

The influence of structure on DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation was studied for the 6-aziridinylpyrrolo[1,2-alpha]benzimidazolequinones (PBIs) and the 6-acetamidopyrrolo[1,2-alpha]benzimidazolequinones (APBIs). The PBIs are reductively activated by DT-diaphorase and alkylate the phosphate backbone of DNA via major groove interactions, while the APBIs are reductively inactivated by this enzyme since only the quinone form inhibits topoisomerase II. Bulk at the 7-position (butyl instead of methyl) significantly decreases k(cat)/K(m) for DT-diaphorase reductase activity for both PBIs and APBIs. As a result, a 7-butyl PBI has little cytotoxicity while the 7-butyl APBI has enhanced cytotoxicity. The type of 3-substituent and the configuration of the 3-position of the PBIs and APBIs influence DT-diaphorase substrate activity to a lesser degree. Bulk at the 7-position (butyl instead of methyl) had an adverse effect on APBI inhibition of topoisomerase II while the configuration of the 3-position had either an adverse or positive effect on inhibition of this enzyme. The configuration of the 3-position, when substituted with a hydrogen bond donor, influences the PBI reductive alkylation of DNA homopolymers. The rationale for this observation is that the R or S stereoisomers will determine if the 3-substituent points in the 3' or 5' direction and thereby influence the hydrogen-bonding interactions. The above findings were used to rationalize the relative cytotoxicity of various PBI and APBI derivatives.
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PMID:Studies of pyrrolo[1,2-alpha]benzimidazolequinone DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation. 913 30