Odell Luke R, Jones Nigel C, Chau Ngoc, Robertson Mark J, Ambrus Joseph I, Deane Fiona M, Young Kelly A, Whiting Ainslie, Xue Jing, Prichard Kate, Daniel James A, Gorgani Nick N, O'Brien Terence J, Robinson Phillip J, McCluskey Adam
Chemistry, Centre for Chemical Biology, School of Environmental & Life Science, The University of Newcastle University Drive Callaghan NSW 2308 Australia
Department of Neuroscience, Central Clinical School, Monash University Melbourne Victoria 3004 Australia.
RSC Med Chem. 2023 Apr 26;14(8):1492-1511. doi: 10.1039/d2md00371f. eCollection 2023 Aug 16.
We show that dansylcadaverine (1) a known in-cell inhibitor of clathrin mediated endocytosis (CME), moderately inhibits dynamin I (dynI) GTPase activity (IC 45 μM) and transferrin (Tfn) endocytosis in U2OS cells (IC 205 μM). Synthesis gave a new class of GTP-competitive dynamin inhibitors, the Sulfonadyns™. The introduction of a terminal cinnamyl moiety greatly enhanced dynI inhibition. Rigid diamine or amide links between the dansyl and cinnamyl moieties were detrimental to dynI inhibition. Compounds with inhibition of dynI activity <10 μM were tested in-cell for inhibition of CME. These data unveiled a number of compounds, analogues 33 (()--(6-{[(3-(4-bromophenyl)-2-propen-1-yl]amino}hexyl)-5-isoquinolinesulfonamide)) and 47 (()--(3-{[3-(4-bromophenyl)-2-propen-1-yl]amino}propyl)-1-naphthalenesulfonamide)isomers that showed dyn IC <4 μM, IC <30 μM and IC from 12-265 μM. Both analogues (33 and 47) are at least 10 times more potent that the initial lead, dansylcadaverine (1). Enzyme kinetics revealed these sulfonamide analogues as being GTP competitive inhibitors of dynI. Sulfonadyn-47, the most potent SVE inhibitor observed (IC = 12.3 μM), significantly increased seizure threshold in a 6 Hz mouse psychomotor seizure test at 30 ( = 0.003) and 100 mg kg ip ( < 0.0001), with similar anti-seizure efficacy to the established anti-seizure medication, sodium valproate (400 mg kg). The Sulfonadyn™ class of drugs target dynamin and show promise as novel leads for future anti-seizure medications.
我们发现，丹磺酰尸胺（1）是一种已知的网格蛋白介导的内吞作用（CME）的细胞内抑制剂，它能适度抑制动力蛋白I（dynI）的GTP酶活性（IC 45 μM），并抑制U2OS细胞中的转铁蛋白（Tfn）内吞作用（IC 205 μM）。合成得到了一类新型的GTP竞争性动力蛋白抑制剂，即磺基动力蛋白™。引入末端肉桂基部分极大地增强了对dynI的抑制作用。丹磺酰基和肉桂基部分之间的刚性二胺或酰胺连接不利于对dynI的抑制作用。对dynI活性抑制<10 μM的化合物进行了细胞内CME抑制测试。这些数据揭示了一些化合物，类似物33（（）--（6-{[（3-（4-溴苯基）-2-丙烯-1-基]氨基}己基）-5-异喹啉磺酰胺））和47（（）--（3-{[3-（4-溴苯基）-2-丙烯-1-基]氨基}丙基）-1-萘磺酰胺）异构体，其dyn IC<4 μM，IC<30 μM，IC为12 - 265 μM。两种类似物（33和47）的效力至少是初始先导化合物丹磺酰尸胺（1）的10倍。酶动力学表明这些磺酰胺类似物是dynI的GTP竞争性抑制剂。磺基动力蛋白-47是观察到的最有效的SVE抑制剂（IC = 12.3 μM），在30（ = 0.003）和100 mg kg腹腔注射时，在6 Hz小鼠精神运动性癫痫测试中显著提高了癫痫阈值（< 0.0001），其抗癫痫疗效与已有的抗癫痫药物丙戊酸钠（400 mg kg）相似。磺基动力蛋白™类药物靶向动力蛋白，有望成为未来抗癫痫药物的新型先导化合物。
