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Molecular Pharmacology

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Research ArticleArticle

Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes

David R. Bauman, Stephen I. Rudnick, Lawrence M. Szewczuk, Yi Jin, Sridhar Gopishetty and Trevor M. Penning
Molecular Pharmacology January 2005, 67 (1) 60-68; DOI: https://doi.org/10.1124/mol.104.006569
David R. Bauman
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Stephen I. Rudnick
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Lawrence M. Szewczuk
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Yi Jin
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Sridhar Gopishetty
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Trevor M. Penning
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Abstract

Human aldo-keto reductases (AKRs) regulate nuclear receptors by controlling ligand availability. Enzymes implicated in regulating ligand occupancy and trans-activation of the nuclear receptors belong to the AKR1C family (AKR1C1-AKR1C3). Nuclear receptors regulated by AKR1C members include the steroid hormone receptors (androgen, estrogen, and progesterone receptors) and the orphan peroxisome proliferator-activated receptor (PPARγ). In human myeloid leukemia (HL-60) cells, ligand access to PPARγ is regulated by AKR1C3, which diverts PGD2 metabolism away from J-series prostanoids (Desmond et al., 2003). Inhibition of AKR1C3 by indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), caused PPARγ-mediated terminal differentiation of the HL-60 cells. To discriminate between antineoplastic effects of NSAIDs that are mediated by either AKR1C or cyclooxygenase (COX) isozymes, selective inhibitors are required. We report a structural series of N-phenylanthranilic acid derivatives and steroid carboxylates that selectively inhibit recombinant AKR1C isoforms but do not inhibit recombinant COX-1 or COX-2. The inhibition constants, IC50, KI values, and inhibition patterns were determined for the NSAID analogs and steroid carboxylates against AKR1C and COX isozymes. Lead compounds, 4-chloro-N-phenylanthranilic acid and 4-benzoyl-benzoic acid for the N-phenylanthranilic acid analogs and most steroid carboxylates, exhibited IC50 values that had greater than 500-fold selectivity for AKR1C isozymes compared with COX-1 and COX-2. Crystallographic and molecular modeling studies showed that the carboxylic acid of the inhibitor ligand was tethered by the catalytic Tyr55-OH2+ and explained why A-ring substituted N-phenylanthranilates inhibited only AKR1C enzymes. These compounds can be used to dissect the role of the AKR1C isozymes in neoplastic diseases and may have cancer chemopreventive roles independent of COX inhibition.

  • Received August 26, 2004.
  • Accepted October 5, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (1)
Molecular Pharmacology
Vol. 67, Issue 1
1 Jan 2005
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Research ArticleArticle

Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes

David R. Bauman, Stephen I. Rudnick, Lawrence M. Szewczuk, Yi Jin, Sridhar Gopishetty and Trevor M. Penning
Molecular Pharmacology January 1, 2005, 67 (1) 60-68; DOI: https://doi.org/10.1124/mol.104.006569

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Research ArticleArticle

Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes

David R. Bauman, Stephen I. Rudnick, Lawrence M. Szewczuk, Yi Jin, Sridhar Gopishetty and Trevor M. Penning
Molecular Pharmacology January 1, 2005, 67 (1) 60-68; DOI: https://doi.org/10.1124/mol.104.006569
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