A sulfoximine-based inhibitor of human asparagine synthetase kills L-asparaginase-resistant leukemia cells
A sulfoximine-based inhibitor of human asparagine synthetase kills L-asparaginase-resistant leukemia cells
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DOI：
10.1016/j.bmc.2012.07.047
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发表时间：
2012-10-01
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;Ahn, Yong-Mo;Richards, Nigel G. J.
已经报道了以纳摩尔效力抑制人天冬酰胺合成酶（hASNS）的腺苷化亚砜亚胺过渡态类似物1在培养基中L-天冬酰胺耗尽时抑制L-天冬酰胺酰胺水解酶（ASNase）抗性MOLT-4白血病细胞系（MOLT-4 R）的增殖。我们现在报告的合成和生物活性的两个新的亚砜亚胺类似物1已被研究的一部分，系统的努力，以确定化合物具有改善的细胞渗透性和/或代谢稳定性。这些新的类似物之一，在细胞pH下没有净电荷的氨基磺酰亚胺5，是比1更好的hASNS抑制剂（K*（I）= 8 nM），并且在低10倍的浓度（IC 50 = 0.1 mM）下抑制MOLT-4 R细胞的增殖。更重要的是，与先导化合物1相反，浓度高于0.25 mM的磺酰亚胺5的存在导致MOLT-4 R细胞死亡，即使培养基中不存在ASNase。当与ASNase敏感性MOLT-4细胞系（MOLT-4S）孵育时，氨基磺酰亚胺5表现出不同的剂量反应行为，支持磺酰亚胺5通过抑制细胞中的hASNS发挥作用的假设。我们的工作提供了进一步的证据，认为hASNS代表了治疗白血病的化疗靶点，也许还有其他癌症，包括前列腺癌。(C)2012爱思唯尔有限公司保留所有权利。
An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an L-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when L-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K*(I) = 8 nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC50 = 0.1 mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25 mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate. (C) 2012 Elsevier Ltd. All rights reserved.