Diarylthiophenes as inhibitors of the pore-forming protein perforin

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• 作者：Christian K. Miller^a ; ^b ; Kristiina M. Huttunen^a ; ^c ; William A. Denny^a ; ^b ; Jagdish K. Jaiswal^a ; Annette Ciccone^d ; Kylie A. Browne^d ; Joseph A. Trapani^d ; ^e ; Julie A. Spicer^a ; ^b ; ^{j.spicer@auckland.ac.nz" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HTS ; high-throughput screen ; SAR ; structure&ndash ; activity relationships ; PRF ; perforin ; CTL ; cytotoxic T lymphocytes ; NK ; natural killer cells ; PAINS ; pan-assay interference compounds ; AgNO3 ; silver(I) nitrate ; KF ; potassium fluoride ; PFP ; pentafluorophenyl ; DCC ; N ; N&prime ; -dicyclohexylcarbodiimide ; HOBt ; hydroxybenzotriazole ; EDCI ; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ; DMF ; dimethylformamide ; KOAc ; potassium acetate ; DMSO ; dimethyl sulfoxide ; THF ; tetrahydrofuran
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：26
• 期：2
• 页码：355-360
• 全文大小：940 K

文摘

Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure–activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class.