Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group.

Aldose reductase, the first enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of aldose reductase was designed, synthesized, and tested for their ability to inhibit aldose reductase and for selectivity relative to structurally related aldehyde reductase. Aldose reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of aldose reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of aldose reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.

Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity.

Inhibition of aldose reductase (AR), the first enzyme of the polyol pathway, is a promising approach in treatment of diabetic complications. We proceeded with optimization of the thioxotriazinoindole scaffold of the novel AR inhibitor cemtirestat by replacement of sulfur with oxygen. A series of 2-(3-oxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl)acetic acid derivatives (OTIs), designed by molecular modeling and docking, were synthesized. More electronegative and less bulky oxygen of OTIs compared to the sulfur of the original thioxotriazinoindole congeners was found to form a stronger H-bond with Leu300 of AR and to render larger rotational flexibility of the carboxymethyl pharmacophore. AR inhibitory activities of the novel compounds were characterized by the IC50 values in a submicromolar range. Markedly enhanced inhibition selectivity relative to the structurally related aldehyde reductase was recorded. To conclude, structure modification of the original carboxymethylated thioxotriazinoindole cemtirestat by isosteric replacement of sulfur with oxygen in combination with variable N(2) simple substituents provided novel analogues with increased AR inhibition efficacy and markedly improved selectivity.

Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands.

BACKGROUND: Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics. ACHIEVEMENTS: Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2-amine skeleton. Their activity against CLK1 (IC50: 20, 30, 40 and 80 nM) and some other CMGC kinases, predicted CLK binding poses, synthesis and physico-chemical characteristics are also stated. Additionally analysis of all PDB available CLK structures and interactions of their ligands was performed. There are only few powerful dual CLK/VEGFR inhibitors known in the literature. We proposed that our inhibitors have similar binding places and interactions in CLK1, 3 and VEGFR2 TK mostly due to the joint N-aryloxazol-2-amine pharmacophoric fragment. One of our N-aryloxazol-2-amines already proved a good activity against both VEGFR2 and CLK1 enzymes (23/80 nM, resp). We proposed that the presented class of compounds has a potential to be developed in dual VEGFR2/CLK clinical compounds with prospective synergy to treat cancer.

Quinoides and VEGFR2 TKIs influence the fate of hepatocellular carcinoma and its cancer stem cells.

Bioactivities of quinoides 1-5 and VEGFR2 TKIs 6-10 in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC50 values in µM concentrations in HCC cells. Quinoide 3 was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor DAPT. However, the more cytotoxic VEFGR TKIs (IC50: 0.4-3.0 µM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor (AF) was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.