Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C

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• 作者：Colleen Carpenter^a ; Roderick J. Sorenson^b ; ^c ; Yafei Jin^b ; ^c ; Szymon Klossowski^d ; Tomasz Cierpicki^d ; Margaret Gnegy^a ; Hollis D. Showalter^b ; ^c ; ^{showalh@umich.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Protein kinase C (PKC) ; Estrogen receptor α (ERα) ; Tamoxifen ; Triarylacrylonitrile derivatives ; Amphetamine ; SAR
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5495-5504
• 全文大小：809 K

文摘

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 ng class="boldFont">6ang> 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 β-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the α and/or α′ 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 β-aryl or β-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the α- or α′-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, ng class="boldFont">6cng>, shows markedly increased potency and selectivity for inhibiting PKC with an IC₅₀ of 80 nM for inhibition of PKC protein substrate and >10 μM for binding to the estrogen receptor α (tamoxifen IC₅₀ = 20 μM and 222 nM, respectively). The data on ng class="boldFont">6cng> provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse.