Small molecule inhibitors of dynamin I GTPase activity: Development of dimeric tyrphostins
Small molecule inhibitors of dynamin I GTPase activity: Development of dimeric tyrphostins
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DOI：
10.1021/jm040208l
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发表时间：
2005-12-01
影响因子：
7.3
通讯作者：
McCluskey, A
中科院分区：
文献类型：
--
作者：
Hill, T;Odell, LR;McCluskey, A
Dynamin I 是内吞作用所需的 GTP 酶，是设计潜在内吞作用抑制剂的绝佳靶标。在我们的实验室中，针对动力蛋白 I 的 GTP 酶活性筛选酪氨酸磷酸酶文库，产生了 mu M 强效先导物，2-氰基-3-(3,4-二羟基苯基)硫代丙烯酰胺（1，IC50 70 mu M）。我们的初步研究表明，只有 1 的二聚体形式表现出动力 I GTP 酶抑制活性。随后的合成迭代基于二聚类似物，并提供了许多小分子、低μM有效的动力蛋白I GTP酶抑制剂，特别是具有至少两个游离酚-OH的对称类似物：儿茶酚-丙烯酰胺（9）（IC50 = 5.1 +/- 0.6μM），其3,4,5-三羟基同源物（10）（IC50 = 1.7） +/- 0.2 μM)，以及相应的3-甲基醚(11) (IC50 = 9 3 μM)。将中心烷基间隔基的长度从乙基增加到丙基(22-24)提供基本上相同的活性，IC 50 分别为1.7±0.2、1.7±0.2和5+/-1μM。在引入己基间隔基之前没有注意到活性降低。我们的研究强调需要两个游离酰胺基 NH，而单 N-甲基 (86) 和双 N-甲基 (87) 类似物均不会抑制动力 I GTP 酶。对于去除腈部分也发现了类似的效果。然而，用9-11的相应酯类似物观察到中等效力：乙酯(90)、丙酯(91)和丁酯(92)，IC50分别为42μM、38μM和61μM。我们的研究揭示了该系列中最有效和最有前途的动力蛋白 I GTP 酶抑制剂 (22)，也称为 BisT。
Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a mu M potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 mu M). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low mu M potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50 = 5.1 +/- 0.6 mu M), its 3,4,5-trihydroxy congener (10) (IC50 = 1.7 +/- 0.2 mu M), and the corresponding 3-methyl ether (11) (IC50 = 9 3 mu M). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50'S of 1.7 0.2, 1.7 0.2, and 5 +/- 1 mu M, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50'S of 42 3, 38 2, and 61 2 mu M, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.