The effect of sulfonate leaving groups on the hypoxia-selective toxicity of nitro analogs of the duocarmycins.

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.

• Authors: Amir Ashoorzadeh, Graham J Atwell, Frederik B Pruijn, William R Wilson, Moana Tercel, William A Denny, Ralph J Stevenson
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 16 Pg. 4851-60 (Aug 15 2011) ISSN: 1464-3391 [Electronic] England
• PMID: 21767954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Alkanesulfonates
• Antineoplastic Agents, Alkylating
• Duocarmycins
• Indoles
• Nitro Compounds
• Prodrugs
• Pyrrolidinones
• DNA
• duocarmycin A

Topics

• Alkanesulfonates (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents, Alkylating (chemical synthesis, chemistry, metabolism, pharmacology)
• Cell Hypoxia (drug effects)
• DNA (chemistry, metabolism)
• Drug Design
• Drug Screening Assays, Antitumor
• Duocarmycins
• Female
• Humans
• Indoles (chemistry, pharmacology)
• Nitro Compounds (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, metabolism, pharmacology)
• Pyrrolidinones (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured