N-substituted glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II (GCP2).
N-substituted glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II (GCP2).
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DOI：
10.1111/j.1747-0285.2011.01085.x
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发表时间：
2011-04
影响因子：
3
通讯作者：
Anderson MO
中科院分区：
文献类型：
--
作者：
Blank BR;Alayoglu P;Engen W;Choi JK;Berkman CE;Anderson MO
谷氨酸羧肽酶II（GCP 2）是一种膜结合的细胞表面肽酶，与多种神经系统疾病有关，也在前列腺肿瘤细胞中过表达。对GCP 2的抑制作为神经保护的一种手段存在显著的兴趣，而GCP 2抑制作为治疗前列腺癌的方法仍然是进一步研究的主题。已充分表征的GCP 2抑制剂类别（膦酸酯和氨基磷酸酯）的关键锌结合官能团是四面体的，并且在中性pH下带负电荷，而谷氨酰脲类抑制剂具有平面和中性锌结合基团。本研究介绍了一类新的GCP 2抑制剂，N-取代的谷氨酰磺酰胺，它具有中性四面体锌结合基序。制备含有15种仲磺酰胺和4种叔（N-甲基）磺酰胺的文库，并评价其对纯化的GCP 2酶活性的抑制效力。虽然大多数抑制剂在100 μM时缺乏效力，但短烷基磺酰胺显示出有希望的低微摩尔效力，该系列中的最佳抑制剂是谷氨酰N-丙基磺酰胺（2 g）。最后，分子对接被用来开发一个模型，以制定这类抑制剂的相对抑制效力的解释。
Glutamate carboxypeptidase II (GCP2) is a membrane-bound cell-surface peptidase which is implicated in several neurological disorders, and is also over-expressed in prostate tumor cells. There is significant interest in the inhibition of GCP2 as a means of neuroprotection, while GCP2 inhibition as a method to treat prostate cancer remains a topic of further investigation. The key zinc-binding functional group of the well characterized classes of GCP2 inhibitors (phophonates and phosphoramidates) is tetrahedral and negatively charged at neutral pH, while glutamyl urea class of inhibitors possess a planar and neutral zinc-binding group. This study introduces a new class of GCP2 inhibitors, N-substituted glutamyl sulfonamides, which possess a neutral tetrahedral zinc-binding motif. A library containing 15 secondary sulfonamides and 4 tertiary (N-methyl) sulfonamides was prepared and evaluated for inhibitory potency against purified GCP2 enzyme activity. While most inhibitors lacked potency at 100 μM, short alkyl sulfonamides exhibited promising low micromolar potency, with the optimal inhibitor in this series being glutamyl N-propylsulfonamide (2g). Lastly, molecular docking was used to develop a model to formulate an explanation for the relative inhibitory potencies employed for this class of inhibitors.
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影响因子：
3.5
作者：
Anderson, Marc O.;Wu, Lisa Y.;Berkman, Clifford E.
通讯作者：
Berkman, Clifford E.
影响因子：
7.3
作者：
Barinka C;Byun Y;Dusich CL;Banerjee SR;Chen Y;Castanares M;Kozikowski AP;Mease RC;Pomper MG;Lubkowski J
通讯作者：
Lubkowski J
影响因子：
3.3
作者：
Haffner, Michael C.;Kronberger, Irmgard E.;Bander, Neil H.
通讯作者：
Bander, Neil H.
影响因子：
3.5
作者：
Maung, J;Mallari, JP;Berkman, CE
通讯作者：
Berkman, CE
影响因子：
5
作者：
Peng, Xiao-Qing;Li, Jie;Xi, Zheng-Xiong
通讯作者：
Xi, Zheng-Xiong