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

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

  • Bioorg Med Chem. 2011 Aug 15;19(16):4851-60. doi: 10.1016/j.bmc.2011.06.073.
Amir Ashoorzadeh 1,  Graham J Atwell,  Frederik B Pruijn,  William R Wilson,  Moana Tercel,  William A Denny,  Ralph J Stevenson
Affiliations

Affiliation

  • 1 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 21767954 DOI: 10.1016/j.bmc.2011.06.073
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.

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