Miller Christian K, Huttunen Kristiina M, Denny William A, Jaiswal Jagdish K, Ciccone Annette, Browne Kylie A, Trapani Joseph A, Spicer Julie A
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
Bioorg Med Chem Lett. 2016 Jan 15;26(2):355-360. doi: 10.1016/j.bmcl.2015.12.003. Epub 2015 Dec 7.
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.
从含呋喃的高通量筛选（HTS）命中化合物（1）进化而来，得到异苯并呋喃-1(3H)-酮（2），它是分离的穿孔素蛋白以及完整的KHYG-1自然杀伤细胞原位递送的穿孔素功能的有效抑制剂。在当前研究中，通过使用取代苯和吡啶基部分作为噻吩（B）-异苯并呋喃酮（C）支架上2-硫代咪唑烷-4-酮（A）的生物电子等排体，继续开展了针对一系列新型二芳基噻吩类似物的构效关系（SAR）研究。对所得化合物进行了体外抑制穿孔素裂解活性能力的测试。羧酰胺（23）对分离的穿孔素的裂解活性比（2）高4倍，为该类化合物的持续研发提供了充分的依据。
