A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase
A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase
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DOI：
10.1016/j.bmc.2009.07.071
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发表时间：
2009-09-15
影响因子：
3.5
通讯作者：
Richards, Nigel G. J.
中科院分区：
文献类型：
--
作者：
Ikeuchi, Hideyuki;Meyer, Megan E.;Richards, Nigel G. J.
具有纳摩尔效力的第一种基于亚砜亚胺的人天冬酰胺合成酶（ASNS）抑制剂已显示在L-天冬酰胺酶存在下抑制天冬酰胺酶抗性MOLT-4细胞的增殖。这验证了文献中关于人ASNS作为抗急性淋巴细胞白血病和卵巢癌新药靶点的可行性的假设。开发这类人ASNS抑制剂的结构-功能关系已被证明是困难的，然而，主要是因为缺乏快速合成程序来构建高度官能化的亚砜亚胺。我们现在报告的条件下，有效地制备这些化合物的偶联亚砜和磺酰胺在铑催化剂的存在下。利用这种方法可以构建两种新的腺苷化磺酰亚胺，预计它们将表现出与原始人ASNS抑制剂相似的结合亲和力和更好的生物利用度。然而，这些化合物的稳态动力学表征揭示了抑制剂上的局部负电荷的重要性，该抑制剂模仿关键酰基腺苷酸反应中间体中的磷酸基团。这些实验对用于筛选实验以获得具有增加的效力和生物利用度的ASNS抑制剂的亚砜亚胺文库的设计施加了重要约束。(C)2009爱思唯尔有限公司保留所有权利。
The first sulfoximine-based inhibitor of human asparagine synthetase (ASNS) with nanomolar potency has been shown to suppress proliferation of asparaginase-resistant MOLT-4 cells in the presence of L-asparaginase. This validates literature hypotheses concerning the viability of human ASNS as a target for new drugs against acute lymphoblastic leukemia and ovarian cancer. Developing structure-function relationships for this class of human ASNS inhibitors has proven diffcult, however, primarily because of the absence of rapid synthetic procedures for constructing highly functionalized sulfoximines. We now report conditions for the efficient preparation of these compounds by coupling sulfoxides and sulfamides in the presence of a rhodium catalyst. Access to this methodology has permitted the construction of two new adenylated sulfoximines, which were expected to exhibit similar binding affinity and better bioavailability than the original human ASNS inhibitor. Steady-state kinetic characterization of these compounds, however, has revealed the importance of a localized negative charge on the inhibitor that mimics that of the phosphate group in a key acyl-adenylate reaction intermediate. These experiments place an important constraint on the design of sulfoximine libraries for screening experiments to obtain ASNS inhibitors with increased potency and bioavailability. (C) 2009 Elsevier Ltd. All rights reserved.