| Abstract
| - The influence of structure on DT-diaphorase substrate activity,topoisomerase II inhibitionactivity, and DNA reductive alkylation was studied for the6-aziridinylpyrrolo[1,2-a]benzimidazolequinones (PBIs) and the6-acetamidopyrrolo[1,2-a]benzimidazolequinones(APBIs). ThePBIs are reductively activated by DT-diaphorase and alkylate thephosphate backbone of DNAvia major groove interactions, while the APBIs are reductivelyinactivated by this enzyme sinceonly the quinone form inhibits topoisomerase II. Bulk at the7-position (butyl instead of methyl)significantly decreaseskcat/Km for DT-diaphorasereductase activity for both PBIs and APBIs.As a result, a 7-butyl PBI has little cytotoxicity while the7-butyl APBI has enhancedcytotoxicity. The type of 3-substituent and the configuration ofthe 3-position of the PBIs andAPBIs 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 oftopoisomerase II whilethe configuration of the 3-position had either an adverse or positiveeffect on inhibition of thisenzyme. The configuration of the 3-position, when substituted witha hydrogen bond donor,influences the PBI reductive alkylation of DNA homopolymers. Therationale for thisobservation is that the R or S stereoisomers willdetermine if the 3-substituent points in the3‘ or 5‘ direction and thereby influence the hydrogen-bondinginteractions. The above findingswere used to rationalize the relative cytotoxicity of various PBI andAPBI derivatives.
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