title: Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide.
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.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
authors.forename: Bingchen
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
authors.forename: Kaili
authors.initials: K
authors.lastname: Ji
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
authors.forename: Vayou
authors.initials: V
authors.lastname: Chittavong
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA. wang@gsu.edu.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
mesh_terms: D004950:Esterases / Q000737:chemistry*; D006862:Hydrogen Sulfide / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000737:chemistry*
chemical_list: D011355:Prodrugs; D004950:Esterases; D006862:Hydrogen Sulfide
keywords: H2S-NSAIDs; anti-inflammatory drugs; enzyme trigger; hydrogen sulfide prodrugs; lactonization
references.citation: Eur J Pharmacol. 2008 Oct 10;594(1-3):1-8
references.pmid: 18680741
references.citation: Nat Rev Drug Discov. 2007 Nov;6(11):917-35
references.pmid: 17948022
references.citation: Chem Commun (Camb). 2014 Jan 18;50(5):587-9
references.pmid: 24280741
references.citation: J Pharm Sci. 1997 Jul;86(7):765-7
references.pmid: 9232513
references.citation: Proc Natl Acad Sci U S A. 1970 Nov;67(3):1143-7
references.pmid: 5274444
references.citation: Chem Sci. 2012 Jan 1;3(8):2412-2420
references.pmid: 23181187
references.citation: Bioorg Chem. 2004 Apr;32(2):109-23
references.pmid: 14990309
references.citation: J Am Chem Soc. 1972 Dec 27;94(26):9175-82
references.pmid: 4642367
references.citation: J Mater Chem B. 2014 Mar 21;2(11):1454-1463
references.pmid: 32261364
references.citation: Circulation. 2013 Mar 12;127(10):1116-27
references.pmid: 23393010
references.citation: Science. 2005 Apr 22;308(5721):518
references.pmid: 15845845
references.citation: Andrologia. 1976;8(1):67-71
references.pmid: 952420
references.citation: J Neurochem. 2010 Apr;113(1):14-26
references.pmid: 20067586
references.citation: Circulation. 2008 May 6;117(18):2351-60
references.pmid: 18443240
references.citation: Biochem Pharmacol. 2013 Jun 1;85(11):1634-43
references.pmid: 23567997
references.citation: J Am Chem Soc. 1972 Dec 27;94(26):9166-74
references.pmid: 4642366
references.citation: J Mol Med (Berl). 2012 Mar;90(3):255-63
references.pmid: 22314625
references.citation: Antioxid Redox Signal. 2010 May 15;12(10):1203-17
references.pmid: 19769484
references.citation: Eur J Biochem. 1999 Jun;262(2):516-21
references.pmid: 10336637
references.citation: Tetrahedron Lett. 2009 Dec 2;50(48):6684-6686
references.pmid: 20160926
references.citation: Acta Pharm Sin B. 2015 Sep;5(5):367-77
references.pmid: 26579468
references.citation: Pharm Res. 1991 Mar;8(3):323-30
references.pmid: 2052518
references.citation: Free Radic Biol Med. 2007 Mar 1;42(5):706-19
references.pmid: 17291994
references.citation: Shock. 2016 Jan;45(1):88-97
references.pmid: 26513708
references.citation: Org Lett. 2015 Sep 4;17(17):4196-9
references.pmid: 26301500
references.citation: Physiol Rev. 2012 Apr;92(2):791-896
references.pmid: 22535897
references.citation: Antioxid Redox Signal. 2010 May 15;12(10):1147-54
references.pmid: 19769459
references.citation: ACS Chem Biol. 2013;8(6):1283-90
references.pmid: 23547844
references.citation: Vascul Pharmacol. 2014 Jan;60(1):32-41
references.pmid: 24287004
references.citation: Chem Commun (Camb). 2014 Oct 14;50(80):11788-805
references.pmid: 25019301
references.citation: J Am Chem Soc. 1972 Dec 27;94(26):9158-65
references.pmid: 4642365
references.citation: Pharmacol Rep. 2007 Jan-Feb;59(1):4-24
references.pmid: 17377202
references.citation: Int J Mol Sci. 2012 Dec 17;13(12):17244-74
references.pmid: 23247285
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17977-82
references.pmid: 17951430
references.citation: Org Lett. 2013 Jun 7;15(11):2786-9
references.pmid: 23697786
references.citation: J Pharm Sci. 2016 Feb;105(2):370-385
references.pmid: 26453244
references.citation: Expert Rev Clin Pharmacol. 2011 Jan;4(1):109-21
references.pmid: 22115352
references.citation: Pharm Res. 1991 Apr;8(4):455-61
references.pmid: 1871039
references.citation: Chemistry. 2014 Jan 20;20(4):1010-6
references.pmid: 24339269
references.citation: J Am Chem Soc. 2011 Jan 12;133(1):15-7
references.pmid: 21142018
references.citation: J Pharm Sci. 2012 Oct;101(10):3979-88
references.pmid: 22833171
references.citation: Biochem Pharmacol. 2013 Mar 1;85(5):689-703
references.pmid: 23103569
references.citation: Bioorg Med Chem. 2012 Apr 15;20(8):2675-8
references.pmid: 22436388
references.citation: ACS Med Chem Lett. 2013 Aug 08;4(10):904-8
references.pmid: 24900583