Synthesis and structure-activity relationships of 2-amino-3-carboxy-4- phenylthiophenes as novel atypical protein kinase C inhibitors

Paul M. Titchenell, H. D. Hollis Showalter, Jean François Pons, Alistair Barber, Yafei Jin, David A. Antonetti

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NFκB driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation.

Original languageEnglish (US)
Pages (from-to)3034-3038
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number10
DOIs
StatePublished - May 15 2013

Fingerprint

Protein C Inhibitor
Structure-Activity Relationship
Protein Kinase Inhibitors
Capillary Permeability
Vascular Endothelial Growth Factor A
Permeability
Protein Isoforms
Blood-Retinal Barrier
Small Molecule Libraries
Molecules
Transcription
Bioactivity
Dextrans
Cell culture
Albumins
Assays
Screening
Blood
Cell Culture Techniques
Genes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Titchenell, Paul M. ; Hollis Showalter, H. D. ; Pons, Jean François ; Barber, Alistair ; Jin, Yafei ; Antonetti, David A. / Synthesis and structure-activity relationships of 2-amino-3-carboxy-4- phenylthiophenes as novel atypical protein kinase C inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 10. pp. 3034-3038.
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Synthesis and structure-activity relationships of 2-amino-3-carboxy-4- phenylthiophenes as novel atypical protein kinase C inhibitors. / Titchenell, Paul M.; Hollis Showalter, H. D.; Pons, Jean François; Barber, Alistair; Jin, Yafei; Antonetti, David A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 10, 15.05.2013, p. 3034-3038.

Research output: Contribution to journalArticle

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