Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2016 Jan 30

PMID 26822005

Citations 49

Authors

Yueqin Zheng

Bingchen Yu

Kaili Ji

Zhixiang Pan

Vayou Chittavong

Binghe Wang

Affiliations

Soon will be listed here.

Abstract

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2 S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2 S prodrugs shows great potential as both research tools and therapeutic agents.

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References

Baskar R, Sparatore A, Del Soldato P, Moore P . Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative inhibit rat vascular smooth muscle cell proliferation. Eur J Pharmacol. 2008; 594(1-3):1-8. DOI: 10.1016/j.ejphar.2008.07.029. View

Szabo C . Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007; 6(11):917-35. DOI: 10.1038/nrd2425. View

Fukushima N, Ieda N, Sasakura K, Nagano T, Hanaoka K, Suzuki T . Synthesis of a photocontrollable hydrogen sulfide donor using ketoprofenate photocages. Chem Commun (Camb). 2013; 50(5):587-9. DOI: 10.1039/c3cc47421f. View

Shan D, Nicolaou M, Borchardt R, Wang B . Prodrug strategies based on intramolecular cyclization reactions. J Pharm Sci. 1997; 86(7):765-7. DOI: 10.1021/js970069d. View

Milstien S, COHEN L . Rate acceleration by stereopopulation control: models for enzyme action. Proc Natl Acad Sci U S A. 1970; 67(3):1143-7. PMC: 283329. DOI: 10.1073/pnas.67.3.1143. View

Levine M, Raines R . Trimethyl lock: A trigger for molecular release in chemistry, biology, and pharmacology. Chem Sci. 2012; 3(8):2412-2420. PMC: 3501758. DOI: 10.1039/C2SC20536J. View

Zych L, Yang W, Liao Y, Griffin K, Wang B . The effect of substitution patterns on the release rates of opioid peptides DADLE and [Leu(5)]-enkephalin from coumarin prodrug moieties. Bioorg Chem. 2004; 32(2):109-23. DOI: 10.1016/j.bioorg.2003.12.002. View

Borchardt R, COHEN L . Stereopopulation control. 3. Facilitation of intramolecular conjugate addition of the carboxyl group. J Am Chem Soc. 1972; 94(26):9175-82. DOI: 10.1021/ja00781a031. View

Bohlender C, Glaser S, Klein M, Weisser J, Thein S, Neugebauer U . Light-triggered CO release from nanoporous non-wovens. J Mater Chem B. 2020; 2(11):1454-1463. DOI: 10.1039/c3tb21649g. View

10.

Kondo K, Bhushan S, King A, Prabhu S, Hamid T, Koenig S . H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013; 127(10):1116-27. PMC: 3670187. DOI: 10.1161/CIRCULATIONAHA.112.000855. View

11.

Blackstone E, Morrison M, Roth M . H2S induces a suspended animation-like state in mice. Science. 2005; 308(5721):518. DOI: 10.1126/science.1108581. View

12.

Roberts T, Masson P, Lauwerys R, Heremans J . Two esterases common to seminal plasma, other external secretions and leucocytes in man. Andrologia. 1976; 8(1):67-71. DOI: 10.1111/j.1439-0272.1976.tb01650.x. View

13.

Gadalla M, Snyder S . Hydrogen sulfide as a gasotransmitter. J Neurochem. 2010; 113(1):14-26. PMC: 2965526. DOI: 10.1111/j.1471-4159.2010.06580.x. View

14.

Li L, Whiteman M, Guan Y, Neo K, Cheng Y, Lee S . Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation. 2008; 117(18):2351-60. DOI: 10.1161/CIRCULATIONAHA.107.753467. View

15.

Testai L, Martelli A, Marino A, DAntongiovanni V, Ciregia F, Giusti L . The activation of mitochondrial BK potassium channels contributes to the protective effects of naringenin against myocardial ischemia/reperfusion injury. Biochem Pharmacol. 2013; 85(11):1634-43. DOI: 10.1016/j.bcp.2013.03.018. View

16.

Borchardt R, COHEN L . Stereopopulation control. II. Rate enhancement of intramolecular nucleophilic displacement. J Am Chem Soc. 1972; 94(26):9166-74. DOI: 10.1021/ja00781a030. View

17.

Vandiver M, Snyder S . Hydrogen sulfide: a gasotransmitter of clinical relevance. J Mol Med (Berl). 2012; 90(3):255-63. PMC: 3901014. DOI: 10.1007/s00109-012-0873-4. View

18.

Calvert J, Coetzee W, Lefer D . Novel insights into hydrogen sulfide--mediated cytoprotection. Antioxid Redox Signal. 2009; 12(10):1203-17. PMC: 2864658. DOI: 10.1089/ars.2009.2882. View

19.

Elleby B, Sjoblom B, Lindskog S . Changing the efficiency and specificity of the esterase activity of human carbonic anhydrase II by site-specific mutagenesis. Eur J Biochem. 1999; 262(2):516-21. DOI: 10.1046/j.1432-1327.1999.00400.x. View

20.

Rao Y, Li X, Nagorny P, Hayashida J, Danishefsky S . A Simple Method for the Conversion of Carboxylic Acids into Thioacids with Lawesson's Reagent. Tetrahedron Lett. 2010; 50(48):6684-6686. PMC: 2762222. DOI: 10.1016/j.tetlet.2009.09.080. View