1,2,3,4-dithiadiazole derivatives as a novel class of calcium signaling modulators.

Aberrant calcium signaling is associated with a diverse range of pathologies, including cardiovascular and neurodegenerative diseases, diabetes, cancer, etc… So, therapeutic strategies based on the correction of pathological calcium signaling are becoming extremely in demand. Thus, the development of novel calcium signaling modulators remains highly actual. Previously we found that 1,2,3,4-dithiadiazole derivative 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide can strongly reduce calcium uptake through store-operated calcium (SOC) channels. Here we tested several structurally related compounds and found that most of them can effectively affect SOC channels and attenuate calcium content in the endoplasmic reticulum, thus, establishing 1,2,3,4-dithiadiazoles as a novel class of SOC channel inhibitors. Comparing different 1,2,3,4-dithiadiazole derivatives we showed that previously published 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide and newly tested 3-(3,5-difluorophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole 2-oxide demonstrated the highest efficacy of SOC entry reduction, supposing the important role of electron-withdrawing substituents to realize the inhibitory activity of 1,2,3,4-dithiadiazoles.

Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress.

Herein, we report that chromone-containing allylmorpholines can affect ion channels formed by pore-forming antibiotics in model lipid membranes, which correlates with their ability to influence membrane boundary potential and lipid-packing stress. At 100 µg/mL, allylmorpholines 1, 6, 7, and 8 decrease the boundary potential of the bilayers composed of palmitoyloleoylphosphocholine (POPC) by about 100 mV. At the same time, the compounds do not affect the zeta-potential of POPC liposomes, but reduce the membrane dipole potential by 80-120 mV. The allylmorpholine-induced drop in the dipole potential produce 10-30% enhancement in the conductance of gramicidin A channels. Chromone-containing allylmorpholines also affect the thermotropic behavior of dipalmytoylphosphocholine (DPPC), abolishing the pretransition, lowering melting cooperativity, and turning the main phase transition peak into a multicomponent profile. Compounds 4, 6, 7, and 8 are able to decrease DPPC's melting temperature by about 0.5-1.9 °C. Moreover, derivative 7 is shown to increase the temperature of transition of palmitoyloleoylphosphoethanolamine from lamellar to inverted hexagonal phase. The effects on lipid-phase transitions are attributed to the changes in the spontaneous curvature stress. Alterations in lipid packing induced by allylmorpholines are believed to potentiate the pore-forming ability of amphotericin B and gramicidin A by several times.

Dithiadiazole derivative 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide - Novel modulator of store-operated calcium entry.

Pathological calcium homeostasis accompanies the development of a large number of different diseases, therefore, the search for new modulators of calcium signaling remains highly actual. Last decades store-operated calcium channels have been repeatedly postulated as a therapeutic target, so the compounds acting on them can be considered promising drug prototypes. Here, we tested several derivatives of 1,2,3,4-dithiadiazole, 1,3-thiazine, pyrazolopyrimidine and thiohydrazides for the ability to affect the thapsigargin-induced calcium response. Using calcium imaging and the patch-clamp technique we found that dithiadiazole derivative3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxidehad a strong inhibitory effect on store-operated calcium entry at the micromolar concentration in HEK293 cells. Moreover, incubation of the cells with this compound also resulted in the decrease of ER calcium content. Thus, we have postulated 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide as a novel inhibitor of store-operated calcium entry and suggested the derivatives of 1,2,3,4-dithiadiazole as a prospective class of compounds for searching new calcium modulators.

A Flexible Synthetic Approach to Fluorescent Chromeno[4,3-b]pyridines and Pyrano[3,2-c]chromenes from Electron-Deficient 3-Vinylchromones.

We report a flexible approach to the synthesis of phenanthrene-like heterocycles through organocatalytic ANRORC (Addition of the Nucleophile, Ring Opening, and Ring Closure) reaction of electron-deficient 3-vinylchromones with cyanoacetamide. Addition of highly basic DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or tetramethylguanidine (TMG) at 80 °C leads to chromeno[4,3-b]pyridines in good yields, whereas Et3 N at 20 °C made it possible to obtain the less accessible pyrano[3,2-c]chromenes and their 2-imines. The synthesis proceeds in mild conditions (EtOH, 20-80 °C), is versatile and applicable for a wide scope of reactants. The obtained compounds show bright fluorescence in the range 460-595 nm with high quantum yields (up to 0.84) in various solvents (MeCN, DMSO, EtOH, H2 O).