H2S-Donating monastrol: A new calcium channel modulator

The H2S and Biginelli’s adducts can be considered as potentials calcium channel modulators.[1,2] In ventricular myocytes, the intracellular Ca2+ transient is responsible for triggering cardiomyocyte contraction.[3] Therefore a hybrid monastrol-H2S (9) was synthetized and evaluated by calcium transient activity (Fig.1). The synthesis of 9, started by Biginelli’s cyclic condensation followed by hydrolyses furnishing 4 (46% yield, 2 steps). The linker 7 was prepared by protecting 2-bromoethan-1-amine with di-tert-butyl-dicarbonate with 73% yield. Then, H2S releasing core 6 was prepared by condensation between trans-anethole and sulfur followed by a methoxy deprotection with 18% yield. The nucleophilic bimolecular substitution of 6 with 7 was followed by an amine deprotection furnishing 8 with 68% yield. Finally, 4 and 8 was coupling providing 9 with 64% yield. The cardiomyocytes was treated using compounds monastrol, 6 and 9 in concentration between 100nM-10mM. The fluctuation in Ca2+ release was recorded in electrically stimulated Fluo4/AM-loaded cardiomyocytes. Monastrol and 9 did not show significance change in the calcium transient. Besides 6, in 100 mM, showed cytotoxic to cardiomyocytes. Fortunately, 9 showed a diminishing of calcium transient comparable with the control nifedipine. In summary, monastrol-H2S was obtained in 5 step with 8% overall yield. The magnitude of the effect evoked by 9 is similar to nifedipine. Therefore, 9 is considered a potential calcium modulator.