Studies of pyrrolo[1,2-alpha]benzimidazolequinone DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation.
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.
Skibo
E B
EB
Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604, USA.
Gordon
S
S
Bess
L
L
Boruah
R
R
Heileman
M J
MJ
D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011809:Quinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011809:Quinones; D059005:Topoisomerase II Inhibitors; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone)