Identifying novel targets in renal cell carcinoma: design and synthesis of affinity chromatography reagents.

Abstract

Two novel scaffolds, 4-pyridylanilinothiazoles (PAT) and 3-pyridylphenylsulfonyl benzamides (PPB), previously identified as selective cytotoxins for von Hippel-Lindau-deficient Renal Carcinoma cells, were used as templates to prepare affinity chromatography reagents to aid the identification of the molecular targets of these two classes. Structure-activity data and computational models were used to predict possible points of attachment for linker chains. In the PAT class, Click coupling of long chain azides with 2- and 3-pyridylanilinothiazoleacetylenes gave triazole-linked pyridylanilinothiazoles which did not retain the VHL-dependent selectivity of parent analogues. For the PPB class, Sonagashira coupling of 4-iodo-(3-pyridylphenylsulfonyl)benzamide with a propargyl hexaethylene glycol carbamate gave an acetylene which was reduced to the corresponding alkyl 3-pyridylphenylsulfonylbenzamide. This reagent retained the VHL-dependent selectivity of the parent analogues and was successfully utilized as an affinity reagent.

• Authors: Muriel Bonnet, Jack U Flanagan, Denise A Chan, Amato J Giaccia, Michael P Hay
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 2 Pg. 711-20 (Jan 15 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24387866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 3-pyridylphenylsulfonyl benzamide
• 4-pyridylanilinothiazole
• Antineoplastic Agents
• Benzamides
• Pyridines
• Sulfones
• Thiazoles

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzamides (chemical synthesis, chemistry, pharmacology)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatography, Affinity
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Kidney Neoplasms (drug therapy, pathology)
• Models, Molecular
• Molecular Structure
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfones (chemical synthesis, chemistry, pharmacology)
• Thiazoles (chemical synthesis, chemistry, pharmacology)