Abstract
Described herein are structure-activity studies of new antitumor agents based on the pyrrolo[1,2-a]benzimidazole (PBI) ring system. These compounds were designed as new DNA cross-linkers mimicking the mitomycin antitumor agents. Actually, the PBI derivatives were found to have anthracycline-like features: (i) shared cross resistance with doxorubicin in a human myeloma line, (ii) cardiotoxicity, and (iii) excellent DNA strand cleaving capability. The DNA strand cleavage is thought to result from reductive alkylation of DNA followed by the generation of reactive oxygen radicals. The best antitumor agent studied is 6-N-aziridinyl-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo- [1,2-a]benzimidazole-5,8-dione 3-acetate (PBI-A), which possesses nanomolar IC50 values against various human ovarian and colon cancer cell lines.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkylation
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Aziridines / chemistry
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Aziridines / pharmacology
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Aziridines / therapeutic use
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Benzimidazoles / therapeutic use
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Colonic Neoplasms / drug therapy
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DNA / drug effects*
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Female
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Free Radicals
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Humans
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Molecular Structure
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Multiple Myeloma / drug therapy
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Ovarian Neoplasms / drug therapy
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Oxidation-Reduction
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Oxygen / metabolism
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Aziridines
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Benzimidazoles
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Free Radicals
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Pyrroles
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6-N-aziridinyl-3-hydrox-7-methyl-2,3-dihydro-1H-pyrrolo(1,2-a)benzimidazole-5,8-dione 3-acetate
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DNA
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Oxygen