Abstract
A series of 3-substituted (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate (nitroCBI) prodrugs containing sulfonate leaving groups undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. They were evaluated (along with chloride leaving group analogs for comparison) for their cytotoxicity against cultures of SKOV3 and HT29 human tumor cell lines under both aerobic and hypoxic conditions. Sulfonates with neutral side chains (e.g., 5,6,7-trimethoxyindole; TMI) show consistently higher hypoxic cytotoxicity ratios (HCRs) (34-246) than the corresponding chloro analogs (2.8-3.1) in SKOV3 cells, but these trends do not hold for compounds with cationic or polar neutral side chains.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkanesulfonates / chemical synthesis
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Alkanesulfonates / chemistry
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Alkanesulfonates / pharmacology
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Antineoplastic Agents, Alkylating / chemical synthesis*
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Antineoplastic Agents, Alkylating / chemistry
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Antineoplastic Agents, Alkylating / metabolism
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Antineoplastic Agents, Alkylating / pharmacology
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Cell Hypoxia / drug effects
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DNA / chemistry
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DNA / metabolism
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Drug Design
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Drug Screening Assays, Antitumor
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Duocarmycins
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Female
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Humans
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Indoles / chemistry*
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Indoles / pharmacology
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Nitro Compounds / chemical synthesis*
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Nitro Compounds / chemistry
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Nitro Compounds / pharmacology
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / metabolism
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Prodrugs / pharmacology
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacology
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Alkanesulfonates
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Antineoplastic Agents, Alkylating
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Duocarmycins
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Indoles
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Nitro Compounds
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Prodrugs
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Pyrrolidinones
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DNA
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duocarmycin A