Design, Synthesis, and Biological Activity of Isophthalic Acid Derivatives Targeted to the C1 Domain of Protein Kinase C

Abstract

Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC delta C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([(3)H]PDBu) from PKC alpha and delta at K(i) values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time, that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.

Euphohelioscopin A Is a PKC Activator Capable of Inducing Macrophage Differentiation

“…This revived the interest in finding molecules able to activate PKC with distinct activities and specificities. More recently, as structural details emerged on the mechanism of PKC activation, several attempts to rationally design PKC activating or inhibiting ligands have been described (Baba et al, 2004; Boije af Gennas et al, 2009; Keck et al, 2010; Kiriazis et al, 2011). In this report we introduce a new scaffold to explore in this context: a lathyrane diterpene.…”

PKC in Regenerative Therapy: New Insights for Old Targets

“…Another class of new synthetic compounds includes isophthalate derivatives (general structure VII , Figure 9) designed by Yli-Kauhaluoma et al through a structure-based approach, easily prepared through four synthetic steps [91]. These molecules are DAG phenylogs, where phorbol ester pharmacophore features are maintained.…”

“…These molecules are DAG phenylogs, where phorbol ester pharmacophore features are maintained. Biological investigations have disclosed their ability to promote neurite outgrowth via the activation of PKC α with K i values ranging from 210 to 920 nM [91]. In particular, compounds 15 and 16 emerged as the most effective compounds (Figure 9) [92].…”

Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors

“…54 The 'thumb II' site binder, filibuvir (FBV; formerly PF 00868554), is a non-nucleoside inhibitor of HCV polymerase, currently in phase II clinical studies. 55,56 VCH-916, VCH759 and VCH-222 (structures not disclosed) are in advanced clinical trials. 57-59 'Palm site I' inhibitors ABT-072, ABT-333, ANA-598 are in phase II development.…”