Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C

Abstract

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKCδ C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain–targeted isophthalates and characterize their binding affinities to the PKCα isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKCα compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.

Multisubstituted pyrimidines effectively inhibit bacterial growth and biofilm formation of Staphylococcus aureus

“…We initially assessed a library of nineteen multisubstituted pyrimidines for antimicrobial activity against planktonic cells as well as biofilms formed by S. aureus ATCC 25923 at the high concentration of 400 µM (all structures and biological data available in Supplementary Table S1 ). Of this library, seventeen compounds were already available, and their syntheses were previously reported by us 20 , while compounds 9a and 10d were prepared following the synthesis described below. Compound 10d was the most potent as it successfully inhibited the planktonic cells and biofilm viability by ≥ 90%.…”

“…2 . As previously reported 20 , we reacted the commercially available diethyl oxalpropionate ( 1 ) and 2-(4-methoxyphenoxy)acetamidine hydrochloride ( 2 ) in the presence of triethylamine (TEA) in absolute ethanol to obtain the pyrimidine 3 containing the PMP-protected hydroxymethyl moiety in position C2 (Fig. 2 ).…”

“…Pyrimidine derivatives have shown a wide spectrum of biological activities including both non-chemotherapeutic, such as cardiovascular 14 and anti-inflammatory 15 , as well as chemotherapeutic, such as anticancer 16 , antiviral 17 , and antibacterial 18 , 19 . In our previous work, we prepared a set of multisubstituted pyrimidines designed to target the C1 domain of protein kinase C 20 . However, a preliminary screening of these derivatives highlighted a potential antibacterial activity.…”

Rigorous Computational Study Reveals What Docking Overlooks: Double Trouble from Membrane Association in Protein Kinase C Modulators

“…5,6 This interaction is mainly governed by hydrogen bonds (H-bonds) between the glycerol backbone of DAG and the protein, most importantly the hydroxy group ( OH) in the sn-3 position of the glycerol (red in Figure 1) and the ester group oxygens in the sn-1 and sn-2 positions (green in Figure 1) and the protein. [7][8][9] Previously, we developed hydrophobic isophthalic acid derivatives (HMIs) as DAG mimetics, in order to achieve the desired modulation in classical and novel isoenzymes of PKC. 8 The ligands in this scaffold possess a trisubstituted phenyl ring with two ester functions in positions 1 and 5, bearing hydrophobic substituents, and a hydroxymethyl moiety ( CH 2 OH) in position 3.…”

“…Surprisingly, the experimental competitive binding assay showed greatly diminished binding for this analog, as PYR-1gP failed to displace [ 3 H]PDBu from PKCα in the presence of phosphatidylserine membranes. 8,9 Failure of the in silico docking study to correctly predict the result of the biological assay is not unexpected, as the technique used is known to be oversimplified. 12 One notable factor that is often dismissed is the effect of the exact environment in which the binding takes place.…”