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

Colleen Carpenter; Roderick J Sorenson; Yafei Jin; Szymon Klossowski; Tomasz Cierpicki; Margaret Gnegy; Hollis D Showalter

doi:10.1016/j.bmc.2016.09.002

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

Bioorg Med Chem. 2016 Nov 1;24(21):5495-5504. doi: 10.1016/j.bmc.2016.09.002. Epub 2016 Sep 4.

Authors

Colleen Carpenter¹, Roderick J Sorenson², Yafei Jin², Szymon Klossowski³, Tomasz Cierpicki³, Margaret Gnegy¹, Hollis D Showalter⁴

Affiliations

¹ Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States.
² 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.
³ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States.
⁴ 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.

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 IC₅₀ of 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.

Keywords: Amphetamine; Estrogen receptor α (ERα); Protein kinase C (PKC); SAR; Tamoxifen; Triarylacrylonitrile derivatives.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Acrylonitrile / chemical synthesis
Acrylonitrile / chemistry
Acrylonitrile / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Protein Binding
Protein Kinase C / antagonists & inhibitors*
Protein Kinase C / metabolism*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tamoxifen / chemistry
Tamoxifen / pharmacology*

Substances

Protein Kinase Inhibitors
Tamoxifen
Protein Kinase C
Acrylonitrile

Abstract

Publication types

MeSH terms

Substances

Grants and funding