Abstract
The disulfide bond possesses unique chemical and biophysical properties which distinguish it as one of the key structural elements of bioactive proteins and peptides, important drugs and other materials. The chemo-selective synthesis of these structures and the exploration of their function have been of longstanding interest to the chemistry community. The past decades have witnessed significant progress in both areas. This review will summarize the historically established and recently developed chemical methods in disulfide bond formation. The discussion will also be extended to the use of the disulfide linkers in small molecules, and peptide- and protein-drug conjugates. It is hoped that the combined overview of the fundamental chemistries and applications to drug discovery will inspire creative thinking and stimulate future novel uses of these versatile chemistries.
Keywords: Sulfur-sulfur bond, disulfide, chemical synthesis, targeted drug discovery, small molecule-drug conjugate, peptide-drug conjugate, protein-drug conjugate and antibody-drug conjugate.
Graphical Abstract
[http://dx.doi.org/10.1038/nrm954] [PMID: 12415301]
[http://dx.doi.org/10.1021/cr200173z] [PMID: 22176580]
[http://dx.doi.org/10.2174/15680266113136660197] [PMID: 24083789]
[http://dx.doi.org/10.1007/s12272-009-1300-4] [PMID: 19387571]
[http://dx.doi.org/10.7164/antibiotics.42.1768] [PMID: 2621160]
[http://dx.doi.org/10.1055/s-2007-969464] [PMID: 4034747]
[http://dx.doi.org/10.1016/0006-2952(89)90663-1] [PMID: 2604751]
[http://dx.doi.org/10.1039/c3cc39062d] [PMID: 23396320]
[PMID: 5735362]
[http://dx.doi.org/ 10.1039/p19730001819] [PMID: 4796650]
[http://dx.doi.org/10.1021/cr400031z] [PMID: 24446748]
[http://dx.doi.org/10.1006/jmbi.1999.3383] [PMID: 10600388]
[http://dx.doi.org/10.1080/14789450.2017.1377613] [PMID: 28879805]
[http://dx.doi.org/10.1007/s41061-018-0184-5] [PMID: 29356979]
[http://dx.doi.org/10.1371/journal.pone.0087366] [PMID: 24520330]
[http://dx.doi.org/10.1586/era.10.88] [PMID: 20645688]
[PMID: 15719846]
[http://dx.doi.org/10.1097/00003081-200009000-00009] [PMID: 10949753]
[http://dx.doi.org/10.2165/00024677-200504030-00004] [PMID: 15898821]
[http://dx.doi.org/10.2174/157488607781668891] [PMID: 18690973]
[http://dx.doi.org/10.1007/s12029-016-9866-9] [PMID: 27619395]
[http://dx.doi.org/10.1038/nrd.2015.36] [PMID: 26988411]
[http://dx.doi.org/10.1182/blood-2017-09-797712] [PMID: 29021230]
[http://dx.doi.org/10.1002/chem.201800681] [PMID: 29645294]
[http://dx.doi.org/10.1007/s41061-018-0193-4] [PMID: 29654469]
[http://dx.doi.org/10.1039/c3ra45997g]
[http://dx.doi.org/10.1055/s-2008-1067188]
[http://dx.doi.org/10.1002/anie.201104305] [PMID: 21898737]
[http://dx.doi.org/10.1021/bc970156x] [PMID: 9548541]
[http://dx.doi.org/10.1002/anie.200701270] [PMID: 17645270]
[http://dx.doi.org/10.1021/bc0100612] [PMID: 11716671]
[http://dx.doi.org/10.1016/S0196-9781(99)00076-5] [PMID: 10477090]
[http://dx.doi.org/10.1111/j.1432-1033.1975.tb02483.x] [PMID: 1204625]
[http://dx.doi.org/10.1016/j.bmc.2004.01.002] [PMID: 14980597]
[http://dx.doi.org/10.1016/0040-4039(96)00019-6]
[http://dx.doi.org/10.1021/jo01046a528]
[http://dx.doi.org/10.1021/ja00017a044]
[http://dx.doi.org/10.1055/s-2002-35634]
[http://dx.doi.org/10.3184/030823405775146988]
[http://dx.doi.org/10.1021/ja972013r]
[http://dx.doi.org/10.1021/ic980348j] [PMID: 11670665]
[http://dx.doi.org/10.1021/jo070099t] [PMID: 17539682]
[http://dx.doi.org/10.1016/S0957-4166(97)00400-X]
[http://dx.doi.org/10.1039/b008734n]
[http://dx.doi.org/10.1021/jo051374j] [PMID: 16292802]
[http://dx.doi.org/10.1071/CH04277]
[http://dx.doi.org/10.1002/anie.201608011] [PMID: 27726267]
[http://dx.doi.org/10.1016/j.tetlet.2011.11.089]
[http://dx.doi.org/10.1039/C5OB00030K] [PMID: 25657109]
[http://dx.doi.org/10.1021/acs.bioconjchem.6b00149] [PMID: 27304609]
[http://dx.doi.org/10.1021/jo00116a001]
[http://dx.doi.org/10.1055/s-1999-3693]
[http://dx.doi.org/10.1039/b305888c] [PMID: 14518908]
[http://dx.doi.org/10.1016/j.catcom.2006.08.036]
[http://dx.doi.org/10.1023/A:1024761324710]
[http://dx.doi.org/10.1016/S0040-4039(03)01402-3]
[http://dx.doi.org/10.1016/j.tetlet.2005.03.040]
[http://dx.doi.org/10.1246/cl.2006.1048]
[http://dx.doi.org/10.1080/17518253.2011.578080]
[http://dx.doi.org/10.1016/j.cclet.2016.03.016]
[http://dx.doi.org/10.1039/b800705e]
[http://dx.doi.org/10.1023/b:rubi.0000023093.05123.31] [PMID: 15143665]
[http://dx.doi.org/10.1074/jbc.M106886200] [PMID: 11551950]
[http://dx.doi.org/10.1074/jbc.M407483200] [PMID: 15294898]
[http://dx.doi.org/10.1002/jps.20253] [PMID: 15570599]
[http://dx.doi.org/10.1080/00397910008087146]
[http://dx.doi.org/10.1081/SCC-120014782]
[http://dx.doi.org/10.1080/10426500802417000] [PMID: 20976042]
[http://dx.doi.org/10.1002/jccs.200700159]
[http://dx.doi.org/10.1021/jo00816a030]
[http://dx.doi.org/10.3184/030823402103170781]
[http://dx.doi.org/10.1055/s-2007-990800]
[http://dx.doi.org/10.1080/10426507.2012.674585]
[http://dx.doi.org/10.1055/s-1980-28912]
[http://dx.doi.org/10.1016/S0040-4039(02)01220-0]
[http://dx.doi.org/10.1039/c3ra43149e]
[http://dx.doi.org/10.1080/17415990903148075]
[http://dx.doi.org/10.1021/jo00063a017]
[http://dx.doi.org/10.1016/j.tetlet.2004.09.100]
[http://dx.doi.org/10.3390/12030694] [PMID: 17851422]
[http://dx.doi.org/10.1016/j.tet.2010.02.077]
[http://dx.doi.org/10.1081/SCC-120028640]
[http://dx.doi.org/10.1016/S0040-4020(01)00960-7]
[http://dx.doi.org/10.1080/10426500490474842]
[http://dx.doi.org/10.1016/S0040-4020(99)00722-X]
[http://dx.doi.org/10.1002/1099-0690(200101)2001:1<131:AID-EJOC131>3.0.CO;2-N]
[http://dx.doi.org/10.1016/j.tet.2011.09.071]
[http://dx.doi.org/10.1016/j.tetlet.2013.07.093]
[http://dx.doi.org/10.1016/j.tetlet.2004.01.006]
[http://dx.doi.org/10.1080/00397910601039267]
[http://dx.doi.org/10.1080/17415990600863778]
[http://dx.doi.org/10.1021/jo960633p] [PMID: 11667478]
[http://dx.doi.org/10.1021/jp1077483] [PMID: 20964425]
[http://dx.doi.org/10.1021/jo200496r] [PMID: 21480642]
[http://dx.doi.org/10.1002/anie.201310249] [PMID: 24470069]
[http://dx.doi.org/10.1021/om200461j]
[http://dx.doi.org/10.1002/adsc.201401010]
[http://dx.doi.org/10.1002/cssc.201600602] [PMID: 27329945]
[http://dx.doi.org/10.1016/j.tetlet.2007.08.094]
[http://dx.doi.org/10.1080/00304940309355362]
[http://dx.doi.org/10.1002/1522-2675(200208)85:8<2559:AID-HLCA2559>3.0.CO;2-9]
[http://dx.doi.org/10.1055/s-2007-965873]
[http://dx.doi.org/10.1021/la063013k] [PMID: 17249705]
[http://dx.doi.org/10.1055/s-2007-990853]
[http://dx.doi.org/10.1055/s-2008-1067118]
[http://dx.doi.org/10.1055/s-1995-5180]
[http://dx.doi.org/10.5012/bkcs.2006.27.11.1900]
[http://dx.doi.org/10.1248/cpb.55.1458] [PMID: 17917289]
[http://dx.doi.org/10.1021/ol0362008] [PMID: 14748594]
[http://dx.doi.org/10.1016/0040-4020(95)00936-1]
[http://dx.doi.org/10.1016/S0960-894X(99)00350-9] [PMID: 10465537]
[http://dx.doi.org/10.1248/cpb.48.1524] [PMID: 11045462]
[http://dx.doi.org/10.1021/ja035221u] [PMID: 12769559]
[http://dx.doi.org/10.1021/ja8049996] [PMID: 18722437]
[http://dx.doi.org/10.1016/j.tetlet.2003.10.120]
[http://dx.doi.org/10.1016/j.tetlet.2004.05.092]
[http://dx.doi.org/10.1016/S0040-4039(00)78510-8]
[http://dx.doi.org/10.1016/S0040-4039(99)01333-7]
[http://dx.doi.org/10.1021/jo00127a017]
[http://dx.doi.org/10.1039/C4RA03592E]
[http://dx.doi.org/10.1016/S0040-4039(02)01915-9]
[http://dx.doi.org/10.1016/S0040-4020(99)00602-X]
[http://dx.doi.org/10.1038/sj.onc.1207508] [PMID: 15021900]
[http://dx.doi.org/10.1055/s-2006-950406]
[http://dx.doi.org/10.1039/C4CC09633A] [PMID: 25604049]
[http://dx.doi.org/10.1021/jo9908492] [PMID: 10813923]
[http://dx.doi.org/10.1021/ol071088p] [PMID: 17608486]
[http://dx.doi.org/10.1021/ja900370y] [PMID: 19256495]
[http://dx.doi.org/10.1021/ol101863s] [PMID: 20731371]
[http://dx.doi.org/10.1039/C0CC02076A] [PMID: 20730241]
[http://dx.doi.org/10.1002/anie.196906771]
[http://dx.doi.org/10.1021/ja00727a048]
[http://dx.doi.org/10.1021/jo01311a055]
[http://dx.doi.org/10.1021/jo00299a010]
[http://dx.doi.org/10.1055/s-1991-20653]
[http://dx.doi.org/10.1080/00397919708004808]
[http://dx.doi.org/10.1055/s-1999-3414]
[http://dx.doi.org/10.1080/10426500108040599]
[http://dx.doi.org/10.1055/s-2005-868488]
[http://dx.doi.org/10.1016/j.tetlet.2009.10.061]
[http://dx.doi.org/10.1080/17415990902725725]
[http://dx.doi.org/10.1016/j.poly.2010.09.033]
[http://dx.doi.org/10.4314/bcse.v17i1.61731]
[http://dx.doi.org/10.1021/jo001392v] [PMID: 11430112]
[http://dx.doi.org/10.1021/jo00074a043]
[http://dx.doi.org/10.1080/00397918208061931]
[http://dx.doi.org/10.1021/jacs.7b09795] [PMID: 29211467]
[http://dx.doi.org/10.1016/j.tetlet.2007.06.074]
[http://dx.doi.org/10.1080/00397919208021143]
[http://dx.doi.org/10.1021/jo00085a025]
[http://dx.doi.org/10.1016/0040-4039(96)01181-1]
[http://dx.doi.org/10.1080/00397919708005447]
[http://dx.doi.org/10.1002/ejoc.200400360]
[http://dx.doi.org/10.1016/S0040-4020(99)00939-4]
[http://dx.doi.org/10.1021/jo0263418] [PMID: 12492347]
[http://dx.doi.org/10.1021/jo0624389] [PMID: 17316050]
[http://dx.doi.org/10.1016/S0040-4039(02)02776-4]
[http://dx.doi.org/10.1080/00397919508015492]
[http://dx.doi.org/10.1021/ic034084z] [PMID: 12793804]
[http://dx.doi.org/10.1016/S0040-4039(01)00789-4]
[http://dx.doi.org/10.3184/030823406778256388]
[http://dx.doi.org/10.1385/0-89603-273-6:91] [PMID: 7894611]
[http://dx.doi.org/10.1002/0471140864.ps1806s23]
[http://dx.doi.org/10.1016/S0076-6879(97)89049-0] [PMID: 9353723]
[http://dx.doi.org/10.1002/ejoc.201402149]
[http://dx.doi.org/10.1016/S0163-7258(96)00198-2] [PMID: 9336012]
[http://dx.doi.org/10.1002/med.10025] [PMID: 12500287]
[http://dx.doi.org/10.3892/ol.2012.1001] [PMID: 23255918]
[http://dx.doi.org/10.1002/anie.201310709] [PMID: 24623670]
[http://dx.doi.org/10.1016/j.drup.2012.07.002] [PMID: 22921318]
[http://dx.doi.org/10.1124/mol.104.003723] [PMID: 15371560]
[http://dx.doi.org/10.1038/nrd4519] [PMID: 25698644]
[http://dx.doi.org/10.1177/1758834015584763] [PMID: 26136852]
[PMID: 21154124]
[http://dx.doi.org/10.1002/ijc.22853] [PMID: 17551919]
[http://dx.doi.org/10.3109/03639045.2012.728226] [PMID: 23039020]
[http://dx.doi.org/10.1038/s41598-018-27320-5] [PMID: 29895863]
[PMID: 9815541]
[http://dx.doi.org/10.1007/s00268-005-0544-5] [PMID: 16555021]
[http://dx.doi.org/10.1021/mp900069d] [PMID: 19361233]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0820] [PMID: 26728408]
[http://dx.doi.org/10.1021/acs.bioconjchem.6b00222] [PMID: 27248781]
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00026] [PMID: 29608845]
[http://dx.doi.org/10.1093/annonc/mdj100] [PMID: 16364960]
[http://dx.doi.org/10.2165/00003495-199754030-00009] [PMID: 9279506]
[http://dx.doi.org/10.1517/14796694.1.1.7] [PMID: 16555971]
[http://dx.doi.org/10.1038/nrc1977] [PMID: 16990856]
[http://dx.doi.org/10.1021/cr900097c] [PMID: 19476377]
[http://dx.doi.org/10.1039/C7BM00382J] [PMID: 28681888]
[http://dx.doi.org/10.1074/jbc.M111.256644] [PMID: 21795678]
[http://dx.doi.org/10.1016/S0304-3835(02)00699-7] [PMID: 12706853]
[http://dx.doi.org/10.1073/pnas.1400749111] [PMID: 24753582]
[http://dx.doi.org/10.3892/ol.2014.1920] [PMID: 24765144]
[http://dx.doi.org/10.3390/molecules22081281] [PMID: 28763044]
[http://dx.doi.org/10.1038/nrd1255] [PMID: 14654798]
[PMID: 23667314]
[http://dx.doi.org/10.1021/acs.jmedchem.8b02036] [PMID: 30735385]
[http://dx.doi.org/10.1124/pr.56.2.6] [PMID: 15169927]
[http://dx.doi.org/10.1517/17460441.1.6.549] [PMID: 23506066]
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00487] [PMID: 26524088]
[http://dx.doi.org/10.1038/nrd3266] [PMID: 20885411]
[http://dx.doi.org/10.1007/s10555-010-9211-x] [PMID: 20112053]
[http://dx.doi.org/10.1038/nrc2748] [PMID: 20029421]
[http://dx.doi.org/10.4155/fmc-2017-0008] [PMID: 28394627]
[http://dx.doi.org/10.1016/j.bmc.2009.11.019] [PMID: 19942441]
[http://dx.doi.org/10.1021/bc100097r] [PMID: 20949910]
[http://dx.doi.org/10.1021/ol1002626] [PMID: 20192275]
[http://dx.doi.org/10.1021/ja303998y] [PMID: 22642558]
[http://dx.doi.org/10.1177/1479164117704380] [PMID: 28423914]
[PMID: 9549761]
[http://dx.doi.org/10.1146/annurev-physiol-021113-170404] [PMID: 24188711]
[http://dx.doi.org/10.3762/bjoc.15.11] [PMID: 30680044]
[http://dx.doi.org/10.1002/(SICI)1099-1387(200003)6:3<97:AID-PSC236>3.0.CO;2-E] [PMID: 10759209]
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0926] [PMID: 24714131]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0804] [PMID: 25231400]
[http://dx.doi.org/10.1200/JCO.2014.57.4244] [PMID: 25584002]
[http://dx.doi.org/10.18632/oncotarget.26135] [PMID: 30344925]
[http://dx.doi.org/10.1016/j.bmc.2018.12.024] [PMID: 30594452]
[http://dx.doi.org/10.3324/haematol.2017.168401] [PMID: 29748443]
[http://dx.doi.org/10.1186/s13045-016-0380-0] [PMID: 28077160]
[http://dx.doi.org/10.1016/j.jim.2013.06.012] [PMID: 23892158]
[http://dx.doi.org/10.1016/j.ejca.2011.02.023] [PMID: 21458984]
[http://dx.doi.org/10.1200/JCO.2003.05.137] [PMID: 12525512]
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0088] [PMID: 15240523]
[http://dx.doi.org/10.1021/acs.bioconjchem.7b00258] [PMID: 28636382]
[http://dx.doi.org/10.1124/pr.54.4.561] [PMID: 12429868]
[http://dx.doi.org/10.1002/jcp.1041560128] [PMID: 8314858]
[http://dx.doi.org/10.1073/pnas.87.9.3410] [PMID: 2333290]
[PMID: 19846912]
[http://dx.doi.org/10.1371/journal.pone.0195542] [PMID: 29649293]