Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates
Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates
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DOI：
10.1016/j.bmc.2004.06.031
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发表时间：
2004-09-15
影响因子：
3.5
通讯作者：
Berkman, CE
中科院分区：
文献类型：
--
作者：
Maung, J;Mallari, JP;Berkman, CE
为了探索远离 PSMA 活性位点的辅助疏水结合寄存器的存在，合成了一系列谷氨酸的苯基烷基膦酰胺衍生物，并评估了它们对 PSMA 的抑制效力。苯基膦酰胺酯和苄基膦酰胺酯（1a 和 1b）仅表现出适度的抑制效力。苯乙基类似物 1c 的抑制效力处于中等水平，而苯环上具有较长烷基链的抑制剂可显着提高 K-i 值。对于其中苯环延伸到距中心磷最远的抑制剂（如果，n=5和1g，n=6），获得了最大的抑制效力。当烷基链从 3 个亚甲基单元增加到 6 个亚甲基单元时出现的轻微锯齿状图案表明，抑制效力并不简单地与苯烷基链赋予的疏水性增加相关，而是一个或多个疏水性结合寄存器可能存在于远离 PSMA 活性位点中的底物识别结构的地方。 (C) 2004 Elsevier Ltd. 保留所有权利。
To explore for the existence of an auxiliary hydrophobic binding register remote from the active site of PSMA a series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA. Both the phenyl- and benzylphosphonamidates (1a and 1b) exhibited only modest inhibitory potency against. The phenethyl analog 1c was intermediate in inhibitory potency while inhibitors possessing a longer alkyl tether from the phenyl ring, resulted in markedly improved K-i values. The greatest inhibitory potency was obtained for the inhibitors in which the phenyl ring was extended furthest from the central phosphorus (if, n = 5 and I g, n = 6). The slightly serrated pattern that emerged as the alkyl tether increased from three to six methylene units suggests that inhibitory potency is not simply correlated to increased hydrophobicity imparted by the phenylalkyl chain, but rather that one or more hydrophobic binding registers may exist remote from the substrate recognition architecture in the active site of PSMA. (C) 2004 Elsevier Ltd. All rights reserved.