Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7,and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.
COBISS.SI-ID: 3370865
Nod1, an important member of the pattern recognition receptor family, remains a virtually unexploited target. Harnessing its innate immune stimulatory properties still remains an unfulfilled goal of medicinal chemistry. Nucleotide-binding oligomerization domain protein 1 (Nod1) agonists have been shown to boost the inflammatory responses against pathogenic microbes and could thus constitute a new class of broad spectrum antimicrobial agents. To gain additional insight into the structure/activity relationships of Nod1 agonistic compounds, a series of novel, conformationally constrained [gama]-D-glutamyl-meso-diaminopimelic acid (iE-DAP) analogs have been designed and synthesized. Ramos-Blue cells expressing Nod1 were used to screen and validate our compounds for their Nod1-agonist activity. Their immunomodulatory properties were subsequently determined in vitro, by evaluating their capacityto induce proinflammatory cytokine and chemokine production from humane peripheral blood mononuclear cells (PBMC), by themselves and in synergy with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand. The synthesized iE-DAP analogs were shown to possess immuno-enhancing properties as a result of their potent and specific Nod1-agonistic effect. The activity of the compound exhibiting the greatest capacity to induce pro-inflammatory cytokine release from PBMC surpassed that of lauroyl-[gama[-D-glutamyl-meso-diaminopimelic acid (C12-iE-DAP).
COBISS.SI-ID: 3506033
Enantiomers of 2,3-dihydro-1,4-benzodioxine derivatives possessing both thrombin and fibrinogen GPIIb/IIIa binding inhibitory activities were prepared from (R)- and (S)-glycidol as potential dual antithrombotic compounds.The influence of chirality and substitution pattern on thrombin inhibition and on inhibition of fibrinogen binding to GPIIb/IIIa was analyzed.Docking studies were used in an attempt to rationalize the results. The (S)-isomers of both 2,3-dihydro-1,4-benzodioxine regioisomers at positions 6 and 7 were found to be better thrombin inhibitors than the corresponding (R)-enantiomers, whereas we observed that stereochemistry does not display a consistent influence on fibrinogen GPIIb/ IIIa binding inhibitory activity. Compound 11b, the (S)-isomer of the 6-substituted regioisomer, possessed the best balanced dual activity, with Ki(thrombin) = 1.67 mikroM and IC50(GPIIb/IIIa) = 0.665 mikroM, raising the hope that merging anticoagulant and platelet antiaggregatory activities in the same molecule could lead to successful multitarget antithrombotic agents.
COBISS.SI-ID: 3391601
Bisphenol A is a monomer used in the production of polycarbonate plastics, epoxy resins and flame retardants. It is an endocrine disruptor with a variety of other effects, including genotoxicity. Oxidative metabolism of bisphenol A yields electophilic bisphenol A-3,4-quinone (BPAQ), which may cause genotoxicity. To determine the genotoxic potential of bisphenol A, the mechanism of the reaction between the BPAQ and deoxyadenosine (dA) was studied in detail. The most probable reaction pathway was determined using quantum chemical methods. Our results demonstrate that the rate limiting step is Michael addition between BPAQ and dA, the main product being the unstable N7-modificated adduct that rapidly undergoes depurination. In addition, our calculations provide strong evidence for protonation of the adducts prior to depurination, which indicates pH dependence of the reaction. The calculated activation barrier for Michael addition is 28.7 kcal/mol, indicating that the reaction with dA is very slow. Comparison with the activation energy of 23.1 kcal/mol for the corresponding deoxyguanosine reaction indicates that most of the DNA damage by BPAQ will occur at the guanine site. The detoxification reactions with glutathione compete with reactions between BPAQ and DNA. The calculated free energy of activation for the reaction with glutathione is significantly lower than that for the corresponding reaction with dA. This indicates that BPAQ will preferably react with glutathione and will only react with DNA when the level of glutathione in the cell is low.
COBISS.SI-ID: 3363185
Voltage-gated sodium channels (VGSC) are attractive targets for drug discoverybecause of the broad therapeutic potential of their modulators. On the basis of the structure of marine alkaloid clathrodin, we have recently discovered novel subtype-selective VGSC modulators I and II that were used as starting points for two different ligand-based virtual screening approaches for discovery of novel VGSC modulators. Similarity searching in the ZINC database of druglike compounds based on compound I resulted in five statedependent Nav1.3 and Nav1.7 modulators with improved activity compared toI (IC50 ( 20 ŽM). Compounds 2 and 16 that blocked sodium permeation in Nav1.7 with IC50 values of 7 and 9 ŽM, respectively, are among the most potent clathrodin analogs discovered so far. In the case of compound II, 3D similarity searching in the same database was followed by docking of an enriched compound library into our human Nav1.4 openpore homology model. Although some of the selected compounds, e.g., 31 and 32 displayed 21% and 22% inactivated state Ipeak block of Nav1.4 at 10 ŽM, respectively, none showed better Nav1.4 modulatory activity than compound II. Taken together, virtual screening yielded compounds 2 and 16, which represent novel scaffolds for the discovery of human Nav1.7 modulators.
COBISS.SI-ID: 3577713