Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C
Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C
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DOI：
10.1016/j.bmc.2016.09.002
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发表时间：
2016-11-01
影响因子：
3.5
通讯作者：
Showalter, Hollis D.
中科院分区：
文献类型：
--
作者：
Carpenter, Colleen;Sorenson, Roderick J.;Showalter, Hollis D.
临床选择性雌激素受体调节剂他莫昔芬也是蛋白激酶 C 的适度抑制剂，蛋白激酶 C 是导致多种无法治疗的脑部疾病（例如苯丙胺滥用）的靶标。这种抑制作用和他莫昔芬穿过血脑屏障的能力使其成为进行进一步 SAR 研究以发现此类疾病的有效疗法的有吸引力的支架。利用已知的化合物6a作为起始模板，并在计算工具的指导下推导已知对中枢神经系统渗透性药物重要的物理化学性质，设计和合成了一系列新型三芳基丙烯腈类似物，提供了相对于他莫昔芬相对于雌激素受体具有增强的PKC效力和选择性的化合物。与经典程序相比，已经开发了包含β-苯环的类似物的缩短合成路线，其中涉及首先在前体二苯甲酮的α和/或α'环上安装二烷基氨基烷氧基侧链，然后将所得酮与苯乙腈阴离子缩合。还开发了利用铃木化学的第二条新颖、高效和通用的路线，该路线将允许在丙烯腈核心上引入各种β-芳基或β-杂芳基部分和侧链取代基。对于在 α 环或 α' 环上具有单侧链的类似物，已经进行了新颖的 2D NMR 实验，可以明确指定 E 和 Z 立体化学。根据 SAR 分析，一种化合物 6c 显示出显着增加的抑制 PKC 的效力和选择性，抑制 PKC 蛋白底物的 IC50 为 80 nM，与雌激素受体 α 结合的 IC50 > 10 μM（他莫昔芬 IC50 分别为 20 μM 和 222 nM）。 6c 的数据为进一步探索 PKC 作为治疗安非他明滥用的药物靶点提供了支持。 (C) 2016 Elsevier Ltd. 保留所有权利。
The clinical selective estrogen receptor modulator tamoxifen is also a modest inhibitor of protein kinase C, a target implicated in several untreatable brain diseases such as amphetamine abuse. This inhibition and tamoxifen's ability to cross the blood brain barrier make it an attractive scaffold to conduct further SAR studies toward uncovering effective therapies for such diseases. Utilizing the known compound 6a as a starting template and guided by computational tools to derive physicochemical properties known to be important for CNS permeable drugs, the design and synthesis of a small series of novel triarylacrylonitrile analogues have been carried out providing compounds with enhanced potency and selectivity for PKC over the estrogen receptor relative to tamoxifen. Shortened synthetic routes compared to classical procedures have been developed for analogues incorporating a beta-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the alpha and/or alpha' rings of a precursor benzophenone and then condensing the resultant ketones with phenylacetonitrile anion. A second novel, efficient and versatile route utilizing Suzuki chemistry has also been developed, which will allow for the introduction of a wide range of beta-aryl or beta-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the alpha- or alpha'-ring, novel 2D NMR experiments have been carried out that allow for unambiguous assignment of E- and Z-stereochemistry. From the SAR analysis, one compound, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50 of 80 nM for inhibition of PKC protein substrate and >10 mu M for binding to the estrogen receptor alpha (tamoxifen IC50 = 20 mu M and 222 nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse. (C) 2016 Elsevier Ltd. All rights reserved.