ACS Medicinal Chemistry Letters
Letter
(10) Caliendo, G.; Cirino, G.; Santagada, V.; Wallace, J. L. Synthesis
and biological effects of hydrogen sulfide (H2S): Development of H2S-
releasing drugs as pharmaceuticals. J. Med. Chem. 2010, 53, 6275−
6286.
(11) Martelli, A.; Testai, L.; Marino, A.; Breschi, M. C.; Da Settimo,
F.; Calderone, V. Hydrogen sulphide: biopharmacological roles in the
cardiovascular system and pharmaceutical perspectives. Curr. Med.
Chem. 2012, 19, 3325−3336.
(12) Benavides, G. A.; Squadrito, G. L.; Mills, R. W.; Patel, H. D.;
Isbell, T. S.; Patel, R. P.; Darley-Usmar, V. M.; Doeller, J. E.; Kraus, D.
W. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl.
Acad. Sci. U.S.A. 2007, 104, 17977−17982.
(13) Zhao, Y.; Wang, H.; Xian, M. Cysteine-activated hydrogen
sulfide (H2S) donors. J. Am. Chem. Soc. 2011, 133, 15−17.
(14) Li, L.; Whiteman, M.; Guan, Y. Y.; Neo, K. L.; Cheng, Y.; Lee, S.
W.; Zhao, Y.; Baskar, R.; Tan, C. H.; Moore, P. K. Characterization of
a novel, water-soluble hydrogen sulfide-releasing molecule
(GYY4137): new insights into the biology of hydrogen sulfide.
Circulation 2008, 117, 2351−2360.
(15) Isenberg, J. S.; Jia, Y.; Field, L.; Ridnour, L. A.; Sparatore, A.; Del
Soldato, P.; Sowers, A. L.; Yeh, G. C.; Moody, T. W.; Wink, D. A.;
Ramchandran, R.; Roberts, D. D. Modulation of angiogenesis by
dithiolethione-modified NSAIDs and valproic acid. Br. J. Pharmacol.
2007, 151, 63−72.
(16) Li, L.; Rossoni, G.; Sparatore, A.; Lee, L. C.; Del Soldato, P.;
Moore, P. K. Anti-inflammatory and gastrointestinal effects of a novel
diclofenac derivative. Free Radical Biol. Med. 2007, 42, 706−719.
(17) Sparatore, A.; Perrino, E.; Tazzari, V.; Giustarini, D.; Rossi, R.;
Rossoni, G.; Erdmann, K.; Schroder, H.; Del Soldato, P. Pharmaco-
logical profile of a novel H2S-releasing aspirin. Free Radical Biol. Med.
2009, 46, 586−592.
vascular effects of H2S, both in in vitro and in vivo experiments.
Specifically, compound 1, which was selected as representative
for investigating the potential vascular effects of all the
analogues of this series, inhibited the NA-induced vaso-
constriction in isolated rat aortic rings, hyperpolarized the
membranes of human HASMCs, and reduced the systolic
blood pressure after oral administration. These thioamide
derivatives might represent useful tools for the rational
development of promising H2S-releasing agents addressed to
the therapeutic treatment of cardiovascular diseases.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthesis, characterization, and pharmacological studies of
compounds 1−12. This material is available free of charge via
AUTHOR INFORMATION
Corresponding Author
(S.T.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This article has been supported by the ‘‘Regional Health
Research Program 2009’’ of Regione Toscana, Italy.
■
(18) Shukla, N.; Rossoni, G.; Hotston, M.; Sparatore, A.; Del
Soldato, P.; Tazzari, V.; Persad, R.; Angelini, G. D.; Jeremy, J. Y. Effect
of hydrogen sulphide-donating sildenafil (ACS6) on erectile function
and oxidative stress in rabbit isolated corpus cavernosum and in
hypertensive rats. BJU Int. 2009, 103, 1522−1529.
ABBREVIATIONS
■
DADS, diallyl disulfide; GYY4137, morpholin-4-ium 4-methox-
yphenyl-morpholino-phosphinodithioate; NA, noradrenaline;
SEM, standard error of mean; VSM, vascular smooth muscle
(19) Wallace, J. L.; Cirino, G.; Santagada, V.; Caliendo, G. Hydrogen
Sulfide Derivatives of Non-Steroidal Anti-Inflammatory Drugs.
WO2008/009127 A1, 2008.
REFERENCES
■
(1) Hosoki, R.; Matsuki, N.; Kimura, H. The possible role of
hydrogen sulfide as an endogenous smooth muscle relaxant in synergy
with nitric oxide. Biochem. Biophys. Res. Commun. 1997, 237, 527−531.
(2) Cheng, Y.; Ndisang, J. F.; Tang, G.; Cao, K.; Wang, R. Hydrogen
sulfide-induced relaxation of resistance mesenteric artery beds of rats.
Am. J. Physiol.: Heart Circ. Physiol. 2004, 287, H2316−2323.
(3) Zhao, W.; Zhang, J.; Lu, Y.; Wang, R. The vasorelaxant effect of
H2S as a novel endogenous gaseous K(ATP) channel opener. EMBO J.
2001, 20, 6008−6016.
(20) Wallace, J. L.; Caliendo, G.; Santagada, V.; Cirino, G. Markedly
reduced toxicity of a hydrogen sulphide-releasing derivative of
naproxen (ATB-346). Br. J. Pharmacol. 2010, 159, 1236−1246.
(21) Dombkowski, R. A.; Russel, M. J.; Olson, K. R. Hydrogen sulfide
as an endogenous regulator of vascular smooth muscle tone in trout.
Am. J. Physiol.: Regul., Integr. Comp. Physiol. 2004, 286, R678−685.
(4) Martelli, A.; Testai, L.; Breschi, M. C.; Lawson, K.; McKay, N. G.;
Miceli, F.; Taglialatela, M.; Calderone, V. Vasorelaxation by hydrogen
sulphide involves activation of Kv7 potassium channels. Pharmacol.
Res. 2013, 70, 27−34.
(5) Yang, G.; Wu, L.; Jiang, B.; Yang, W.; Qi, J.; Cao, K.; Meng, Q.;
Mustafa, A. K.; Mu, W.; Zhang, S.; Snyder, S. H.; Wang, R. H2S as a
physiologic vasorelaxant: hypertension in mice with deletion of
cystathionine gamma-lyase. Science 2008, 322, 587−590.
(6) Zhong, G.; Chen, F.; Cheng, Y.; Tang, C.; Du, J. The role of
hydrogen sulfide generation in the pathogenesis of hypertension in rats
induced by inhibition of nitric oxide synthase. J. Hypertens. 2003, 21,
1879−1885.
(7) Martelli, A.; Testai, L.; Breschi, M. C.; Blandizzi, C.; Virdis, A.;
Taddei, S.; Calderone, V. Hydrogen sulphide: novel opportunity for
drug discovery. Med. Res. Rev. 2012, 32, 1093−1130.
(8) Pan, L. L.; Liu, X. H.; Gong, Q. H.; Yang, H. B.; Zhu, Y. Z. Role
of cystathionine γ-lyase/hydrogen sulfide pathway in cardiovascular
disease: A novel therapeutic strategy? Antioxid. Redox Signaling 2012,
17, 106−118.
(9) Li, Y. F.; Xiao, C. S.; Hui, R. T. Calcium sulphide (CaS), a donor
of hydrogen sulphide (H2S): a new antihypertensive drug? Med.
Hypotheses 2009, 73, 445−447.
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