A small library of arylthioamides 1−12 was easily synthesized, and their H 2 S-releasing properties were evaluated both in the absence or in the presence of an organic thiol such as L-cysteine. A number of arylthioamides (1−3 and 7) showed a slow and L-cysteine-dependent H 2 S-releasing mechanism, similar to that exhibited by the reference slow H 2 S-releasing agents, such as diallyl disulfide (DADS) and the phosphinodithioate derivative GYY 4137. Compound 1 strongly abolished the noradrenaline-induced vasoconstriction in isolated rat aortic rings and hyperpolarized the membranes of human vascular smooth muscle cells in a concentration-dependent fashion. Finally, a significant reduction of the systolic blood pressure of anesthetized normotensive rats was observed after its oral administration. Altogether these results highlighted the potential of arylthioamides 1−3 and 7 as H 2 S-donors for basic studies, and for the rational design/development of promising pharmacotherapeutic agents to treat cardiovascular diseases.

Hydrogen sulphide (H(2)S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H(2)S is biosynthesized in mammalian tissues by cystathionine-β-synthase and cystathionine-γ-lyase. H(2)S exhibits the antioxidant properties of inorganic and organic sulphites, behaving as a scavenger of reactive oxygen species. There is also clear evidence that H(2)S triggers other important effects, mainly mediated by the activation of ATP-sensitive potassium channels (K(ATP)). This mechanism accounts for the vasorelaxing and cardioprotective effects of H(2)S. Furthermore, H(2)S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H(2)S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H(2)S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H(2)S biosynthesis is involved in CV complications associated with diabetes mellitus. There is also evidence of a cross-talk between the H(2)S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H(2 S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2)S have led several authors to look at this mediator as "the new NO" that has given attractive opportunities to develop innovative classes of drugs. In this review, the main biological actions of H(2)S are discussed. Moreover, some examples of H(2)S-donors are shown, as well as some hybrids, in which H(2)S-releasing moieties are added to well-known drugs, for improving their pharmacodynamic profile or reducing the potential for adverse effects, are reported.

a b s t r a c tHydrogen sulfide (H 2 S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial.The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H 2 S donors (the natural allyl-isothiocyanate and the synthetics phenyl-and carboxyphenylisothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied.Mice were treated with paclitaxel (2.0 mg kg À1) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg À1) was administered i.p. on days 1e2, 5e9, 12e14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H 2 S donors (1.33, 4.43, 13.31 mmol kg À1 ) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H 2 S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the Slacking molecule allyl-isocyanate did not increase pain threshold; the H 2 S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H 2 S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H 2 S donors.Sistemically-or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H 2 S. Activation of Kv7 channels largely mediate the anti-neuropathic effect.

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