title: Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C.
abstract: 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 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, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50of 80nM for inhibition of PKC protein substrate and >10μM for binding to the estrogen receptor α (tamoxifen IC50=20μM and 222nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Colleen
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Sorenson
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Szymon
authors.initials: S
authors.lastname: Klossowski
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Gnegy
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States; Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: showalh@umich.edu.
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
mesh_terms: D000181:Acrylonitrile / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; D011493:Protein Kinase C; D000181:Acrylonitrile
keywords: Amphetamine; Estrogen receptor α (ERα); Protein kinase C (PKC); SAR; Tamoxifen; Triarylacrylonitrile derivatives