Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase.
Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase.
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细胞色素 P450 4F11 激活的硬脂酰辅酶 A 去饱和酶抑制剂的发现。
DOI：
10.1021/acs.jmedchem.8b00052
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发表时间：
2018
影响因子：
7.3
通讯作者：
Ready,JosephM
中科院分区：
文献类型：
--
作者：
Winterton,SarahE;Capota,Emanuela;Wang,Xiaoyu;Chen,Hong;Mallipeddi,PremaL;Williams,NoelleS;Posner,BruceA;Nijhawan,Deepak;Ready,JosephM
硬脂酰辅酶A去饱和酶(SCD)催化饱和脂肪酸转化为不饱和脂肪酸的第一步。不饱和脂肪酸是细胞膜完整性和细胞增殖所必需的。出于这些原因，SCD的抑制剂代表了癌症的潜在治疗方法。然而，系统活性的SCD抑制剂会导致皮肤毒性，这是其发展的障碍。我们最近描述了一系列草酸二酰胺，它们通过CYP4F11介导的代谢在一组癌症中转化为活性的SCD抑制剂。在这里，我们描述了草酸二酰胺和相关的N-酰基脲的优化，并分析了与代谢激活和SCD抑制相关的构效关系。
Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and relatedN-acyl ureas and an analysis of the structure–activity relationships related to metabolic activation and SCD inhibition.
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影响因子：
19
作者：
Ackerman, Daniel;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
影响因子：
4.2
作者：
Miyazaki, M;Man, WC;Ntambi, JM
通讯作者：
Ntambi, JM
影响因子：
7.3
作者：
Hirsh, Andrew J.;Molino, Bruce F.;Johnson, M. Ross
通讯作者：
Johnson, M. Ross
影响因子：
7.3
作者：
Zaihui Zhang;Shaoyi Sun;Vishnumurthy Kodumuru;Duanjie Hou;Shifeng Liu;Nagasree Chakka;S. Sviridov;S. Chowdhury;D. McLaren;L. Ratkay;Kuldip Khakh;Xing Cheng;H. Gschwend;R. Kamboj;Jianmin Fu;M. Winther
通讯作者：
Zaihui Zhang;Shaoyi Sun;Vishnumurthy Kodumuru;Duanjie Hou;Shifeng Liu;Nagasree Chakka;S. Sviridov;S. Chowdhury;D. McLaren;L. Ratkay;Kuldip Khakh;Xing Cheng;H. Gschwend;R. Kamboj;Jianmin Fu;M. Winther
影响因子：
8.8
作者：
Kim H;Rodriguez-Navas C;Kollipara RK;Kapur P;Pedrosa I;Brugarolas J;Kittler R;Ye J
通讯作者：
Ye J