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Bioorg Med Chem. 2014 Jan 15;22(2):711-20. doi: 10.1016/j.bmc.2013.12.028. Epub 2013 Dec 20.

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

Author information

1
Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
2
Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
3
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. Electronic address: m.hay@auckland.ac.nz.

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.

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

PMID:
24387866
PMCID:
PMC5713883
DOI:
10.1016/j.bmc.2013.12.028
[Indexed for MEDLINE]
Free PMC Article

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