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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.

Original publication

DOI

10.1016/j.bmc.2013.12.028

Type

Journal article

Journal

Bioorg Med Chem

Publication Date

15/01/2014

Volume

22

Pages

711 - 720

Keywords

BOC, Click chemistry, DCM, DMF, GLUT-1, HTS, PAT, PEG, PPB, RCC, Renal cell carcinoma, SAR, Sonogashira cross coupling, TBTA, TFA, THF, TMS, Von Hippel–Lindau factor, dichloromethane, dimethylformamide, high throughput screening, polyethylene glycol, pyridylanilino thiazole, pyridylphenylsulfonyl benzamides, renal cell carcinoma, structure–activity relationship, tert-butyloxycarbonyl, tetrahydrofuran, trifluoroacetic acid, trimethylsilyl, tris-(benzyltriazolyl)amine, Antineoplastic Agents, Benzamides, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Proliferation, Chromatography, Affinity, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Humans, Kidney Neoplasms, Models, Molecular, Molecular Structure, Pyridines, Structure-Activity Relationship, Sulfones, Thiazoles