Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents |
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| Institution: | 1. Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. 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;1. Micro-Optoelectronic and Nanostructures Laboratory, Department of physics, Faculty of Sciences, Monastir University Environment Street, 5019 Monastir, Tunisia;2. Micro-Optoelectronic and Nanostructures Laboratory, University of Sousse, Tunisia;1. Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716-2586, USA;2. Department of Computer Science, National University of Singapore, Singapore 117417, Republic of Singapore;3. Kurt Gödel Research Center for Mathematical Logic, Vienna, Austria;4. Department of Mathematics, National University of Singapore, Singapore 119076, Republic of Singapore;1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China;2. Institutes of Biomedical Sciences Fudan University, 138 Yixueyuan Road, Shanghai 200032, China;3. Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China;4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Institute of Mental Health, 600 South Wan Ping Road, Shanghai 200030, China |
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| 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. |
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| Keywords: | Click chemistry Sonogashira cross coupling Renal cell carcinoma Von Hippel–Lindau factor GLUT-1 |
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