Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators

Abstract

Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.

Rap1 Small GTPase Regulates Vascular Endothelial-Cadherin-Mediated Endothelial Cell–Cell Junctions and Vascular Permeability

“…95) In fact, non-cyclic nucleotide and low-molecular weight compounds that activate Epac have recently been developed, though their efficacies for improving vascular barrier function in animal disease models have not yet been adequately tested. [96][97][98] Therefore, low-molecular weight compounds with the capacity to activate Rap1 signaling, e.g., Epac activators, might be ideal agents for treating the various diseases associated with vascular hyperpermeability.…”

Decoding Directing Groups and Their Pivotal Role in C−H Activation

“…[261,278] The free À NH 2 sulfonamide can be readily synthesized after treatment of the benzenesulfonyl chloride with ammonium hydroxide (Scheme 55). [279] Sahoo group has been employing methylphenyl-sulfoximines as an easily attachable and detachable directing group for CÀ H functionalization. [265] To test the effectiveness of this directing group, Sahoo and co-authors submitted the substrate to known reaction conditions in a palladium-catalyzed ortho-C(sp 2 )À H acetoxylation, generating new acetoxylated products with moderate yields.…”

“…The free − NH 2 sulfonamide can be readily synthesized after treatment of the benzenesulfonyl chloride with ammonium hydroxide (Scheme 55). [279] …”

Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?

“…Among them, compounds 25e, 25f, 25n, and 25u show a higher selectivity over EPAC1. Specifically, the agonist 25u inhibits STAT3 activation, and subsequent pro-inflammatory IL-6 signaling to Vascular cell adhesion protein 1 (VCAM1) induction, showing a higher activity than its precursor I942 [ 35 ]. Another non-cyclic nucleotide, SY009 agonist was isolated by ultra HTS in a library of 350,000 compounds.…”