Abstract
Cancer is becoming more common worldwide, impacting the vast majority of people. As a result, new anticancer drugs are currently being created, and their safety is still being assessed. Pyrazine-based medications are a substantial contribution, as they are one of the most important pharmacophores found in heterocyclic compounds both synthetically and naturally. It's a six-membered aromatic heterocycle with two nitrogen atoms with a wide range of therapeutic applications in drug development and numerous prospects for future enhancement in anticancer drugs by targeting several critical receptors. A number of pyrazine compounds have been shown to inhibit enzymes, receptors, and a range of additional cancer-fighting targets. Researchers are currently focused on the creation of pyrazine-based novel derivatives for cancer treatment in combination with other moieties. As a result, this review illuminates the recent therapeutic expansion of pyrazine-based drugs, as well as their synthetic schemes, tabulated detailed clinical trial drugs, marketed drugs with their primary target, and a list of recently patented and published research papers, all of which will help scientists build successful medications with the appropriate pharmacological activity.
Keywords: Pyrazine moiety, heterocyclic compound, synthetic scheme, anticancer, cancer treatment, pyrazine-based drugs.
[http://dx.doi.org/10.1038/483531a] [PMID: 22460880]
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[http://dx.doi.org/10.1093/jnci/djaa069] [PMID: 32433739]
[http://dx.doi.org/10.1016/S2214-109X(19)30488-7] [PMID: 31862245]
[http://dx.doi.org/10.1016/j.tips.2017.06.005] [PMID: 28709554]
[http://dx.doi.org/10.1016/j.mehy.2005.11.036] [PMID: 16414204]
[http://dx.doi.org/10.1001/jamanetworkopen.2021.38793] [PMID: 34905002]
[http://dx.doi.org/10.1016/j.chembiol.2017.08.002] [PMID: 28938087]
[http://dx.doi.org/10.1002/jhet.5570230254]
[http://dx.doi.org/10.1111/cbdd.12382] [PMID: 24954298]
[http://dx.doi.org/10.1016/S0065-2725(08)60953-8]
[http://dx.doi.org/10.1038/193776a0] [PMID: 14458748]
[http://dx.doi.org/10.1002/aoc.2837]
[http://dx.doi.org/10.1021/jm00351a008] [PMID: 7131483]
[http://dx.doi.org/10.1016/j.tet.2010.08.036]
[http://dx.doi.org/10.1021/jm070776b] [PMID: 18473434]
[http://dx.doi.org/10.1002/cber.187600902218]
[http://dx.doi.org/10.1021/jf60228a058]
[http://dx.doi.org/10.1128/MCB.25.8.2873-2884.2005] [PMID: 15798178]
[http://dx.doi.org/10.1016/j.clinthera.2016.03.026] [PMID: 27158009]
[PMID: 24883085]
[http://dx.doi.org/10.21037/tcr.2017.10.30]
[http://dx.doi.org/10.1186/s40169-018-0185-6] [PMID: 29541939]
[PMID: 30568933]
[http://dx.doi.org/10.1016/j.jrras.2015.03.003]
[http://dx.doi.org/10.18388/abp.2005_3421] [PMID: 16175236]
[http://dx.doi.org/10.1016/j.ejmech.2014.08.016] [PMID: 25113876]
[http://dx.doi.org/10.1007/BF02969297] [PMID: 17225456]
[http://dx.doi.org/10.1063/1.3059906]
[http://dx.doi.org/10.1021/cb500846u] [PMID: 25562692]
[http://dx.doi.org/10.1002/JLB.2RU1118-422R] [PMID: 30605226]
[http://dx.doi.org/10.3390/cells9030780] [PMID: 32210140]
[http://dx.doi.org/10.4155/fmc.12.3] [PMID: 22416777]
[http://dx.doi.org/10.3390/ijms23010369] [PMID: 35008795]
[http://dx.doi.org/10.1016/j.ijrobp.2003.11.041] [PMID: 15142631]
[http://dx.doi.org/10.1172/JCI32278] [PMID: 17671639]
[http://dx.doi.org/10.1016/j.molstruc.2020.128013]
[http://dx.doi.org/10.1038/nrc.2017.8] [PMID: 28303906]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2329] [PMID: 26078430]
[http://dx.doi.org/10.1016/j.ctrv.2016.03.015] [PMID: 27109926]
[http://dx.doi.org/10.1016/j.tips.2016.10.003] [PMID: 27992319]
[http://dx.doi.org/10.1053/j.seminoncol.2015.09.027] [PMID: 26615127]
[http://dx.doi.org/10.1016/j.apsb.2018.12.008] [PMID: 30972282]
[http://dx.doi.org/10.3390/molecules23030698] [PMID: 29562726]
[http://dx.doi.org/10.5732/cjc.011.10111] [PMID: 21718592]
[http://dx.doi.org/10.3389/fcell.2020.564601] [PMID: 33015058]
[PMID: 20187324]
[http://dx.doi.org/10.1002/14651858.CD001929.pub3]
[http://dx.doi.org/10.1016/j.ejmech.2019.111988] [PMID: 31901746]
[PMID: 2284096]
[PMID: 1565476]
[http://dx.doi.org/10.1038/nature00766] [PMID: 12068308]
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0366] [PMID: 19671735]
[http://dx.doi.org/10.2174/1568011023354290] [PMID: 12678749]
[http://dx.doi.org/10.1016/j.ejmech.2018.01.042] [PMID: 29407956]
[http://dx.doi.org/10.1517/13543776.15.9.1169]
[http://dx.doi.org/10.1242/jcs.013136] [PMID: 17715155]
[http://dx.doi.org/10.1242/jcs.03145] [PMID: 16912073]
[http://dx.doi.org/10.1038/nrm1245] [PMID: 14625535]
[http://dx.doi.org/10.1016/j.febslet.2005.04.080] [PMID: 15922328]
[http://dx.doi.org/10.1016/j.bmc.2020.115351] [PMID: 32035750]
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0013] [PMID: 18852116]
[http://dx.doi.org/10.2165/00003495-200969020-00006] [PMID: 19228077]
[http://dx.doi.org/10.1038/onc.2008.362] [PMID: 18794803]
[http://dx.doi.org/10.3892/mmr.2013.1781] [PMID: 24213221]
[http://dx.doi.org/10.1039/C8RA08246D] [PMID: 35558629]
[http://dx.doi.org/10.1517/13543784.17.7.997] [PMID: 18549337]
[http://dx.doi.org/10.1200/JCO.2011.40.3774] [PMID: 22869872]
[http://dx.doi.org/10.2174/1389557521666210614162031] [PMID: 34126914]
[http://dx.doi.org/10.1038/nrc3205] [PMID: 22270953]
[http://dx.doi.org/10.2174/1570180819666220117123958]
[http://dx.doi.org/10.1038/nrm3012] [PMID: 21102609]
[http://dx.doi.org/10.1517/13543776.17.9.1035]
[http://dx.doi.org/10.1016/j.ejmech.2017.08.044] [PMID: 29157685]
[http://dx.doi.org/10.1016/j.bioorg.2020.104356] [PMID: 33142417]
[http://dx.doi.org/10.1039/D0NJ00575D]
[http://dx.doi.org/10.1016/S0021-9258(17)41838-2] [PMID: 8106347]
[http://dx.doi.org/10.1021/bi00250a039] [PMID: 7947793]
[PMID: 9850056]
[http://dx.doi.org/10.1016/j.canlet.2006.03.007] [PMID: 16621243]
[http://dx.doi.org/10.1016/j.bmc.2022.116761] [PMID: 35504208]
[http://dx.doi.org/10.1039/D2RA01198K] [PMID: 35424971]
[http://dx.doi.org/10.1007/s00044-021-02745-2]
[http://dx.doi.org/10.1016/j.ejca.2010.04.002] [PMID: 20418096]
[http://dx.doi.org/10.1016/j.bmc.2019.03.018] [PMID: 30878193]
[http://dx.doi.org/10.1126/science.270.5244.2008] [PMID: 8533096]
[http://dx.doi.org/10.1074/jbc.272.13.8141] [PMID: 9079627]
[http://dx.doi.org/10.1038/18465] [PMID: 10094049]
[http://dx.doi.org/10.1126/science.272.5265.1179] [PMID: 8638164]
[http://dx.doi.org/10.1016/S1097-2765(00)80244-0] [PMID: 10882101]
[http://dx.doi.org/10.1016/j.ejmech.2018.12.025] [PMID: 30576901]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01714] [PMID: 29683667]
[http://dx.doi.org/10.1016/j.bmc.2018.05.004] [PMID: 30115493]
[PMID: 28164761]
[http://dx.doi.org/10.4161/cbt.10.7.12965] [PMID: 20686366]
[http://dx.doi.org/10.1073/pnas.1008136107] [PMID: 20679220]
[http://dx.doi.org/10.1038/ncomms6413] [PMID: 25403230]
[http://dx.doi.org/10.1016/j.bmc.2019.02.007] [PMID: 30824167]
[http://dx.doi.org/10.1146/annurev.biochem.70.1.503] [PMID: 11395416]
[http://dx.doi.org/10.2174/1389557521666211022145458] [PMID: 34719361]
[http://dx.doi.org/10.1042/bst0310474] [PMID: 12653666]
[http://dx.doi.org/10.1021/jm801329v] [PMID: 19348473]
[http://dx.doi.org/10.1080/14756366.2022.2052868] [PMID: 35506234]
[http://dx.doi.org/10.1146/annurev.biochem.68.1.1015] [PMID: 10872471]
[http://dx.doi.org/10.3390/ph15050502] [PMID: 35631329]
[http://dx.doi.org/10.1016/j.canlet.2014.12.035] [PMID: 25528630]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00168] [PMID: 26340601]
[http://dx.doi.org/10.1038/nchembio.2143] [PMID: 27479743]
[http://dx.doi.org/10.1111/cas.13928] [PMID: 30618169]
[http://dx.doi.org/10.1038/s41598-017-06378-7] [PMID: 28729678]
[http://dx.doi.org/10.1042/BSR20181476] [PMID: 30509961]
[http://dx.doi.org/10.1002/mc.22799] [PMID: 29569755]
[http://dx.doi.org/10.3892/ol.2018.7932] [PMID: 29552147]
[http://dx.doi.org/10.3892/mmr.2017.7637] [PMID: 28983605]
[http://dx.doi.org/10.1038/s41598-017-04366-5] [PMID: 28680051]
[http://dx.doi.org/10.15252/embj.201899735] [PMID: 30209241]
[http://dx.doi.org/10.1016/j.ccr.2006.04.023] [PMID: 16766262]
[http://dx.doi.org/10.1073/pnas.0914433107] [PMID: 20133848]
[http://dx.doi.org/10.1016/j.ejmech.2019.05.033] [PMID: 31129449]
[http://dx.doi.org/10.1146/annurev.biochem.72.121801.161629] [PMID: 12676795]
[http://dx.doi.org/10.1007/978-1-61779-536-7_1]
[http://dx.doi.org/10.1007/978-3-642-45106-5_5]
[http://dx.doi.org/10.1038/368246a0] [PMID: 8145823]
[http://dx.doi.org/10.1016/j.bbr.2014.08.011] [PMID: 25127683]
[http://dx.doi.org/10.1002/(SICI)1098-1136(199904)26:2<153:AID-GLIA6>3.0.CO;2-Z] [PMID: 10384880]
[http://dx.doi.org/10.1016/j.ejmech.2019.06.064] [PMID: 31271959]
[http://dx.doi.org/10.1016/0092-8674(92)90191-E] [PMID: 1346755]
[http://dx.doi.org/10.1093/nar/20.10.2603] [PMID: 1350857]
[http://dx.doi.org/10.1016/j.cell.2012.02.013] [PMID: 22464331]
[http://dx.doi.org/10.1038/nrd4286] [PMID: 24751816]
[http://dx.doi.org/10.1371/journal.pone.0033834] [PMID: 22442726]
[http://dx.doi.org/10.1016/j.tig.2014.05.001] [PMID: 24932742]
[http://dx.doi.org/10.1056/NEJMoa1301689] [PMID: 23634996]
[http://dx.doi.org/10.1038/nature09639] [PMID: 21248752]
[PMID: 11085541]
[http://dx.doi.org/10.1002/humu.20730] [PMID: 18386774]
[http://dx.doi.org/10.1016/j.cell.2012.08.029] [PMID: 22980975]
[http://dx.doi.org/10.1038/28212] [PMID: 9671307]
[PMID: 9892189]
[http://dx.doi.org/10.1016/j.ccr.2013.12.007] [PMID: 24434208]
[http://dx.doi.org/10.1186/1476-4598-7-58] [PMID: 18559093]
[http://dx.doi.org/10.1002/hep.26540] [PMID: 23728943]
[http://dx.doi.org/10.1016/j.bmc.2019.02.045] [PMID: 30824168]
[http://dx.doi.org/10.1182/blood-2011-02-333773] [PMID: 22025527]
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0397] [PMID: 22966017]
[http://dx.doi.org/10.1517/13543784.13.7.743] [PMID: 15212616]
[http://dx.doi.org/10.1016/j.drudis.2010.05.001] [PMID: 20553955]
[http://dx.doi.org/10.1517/13543770903207039]
[http://dx.doi.org/10.1517/13543776.2010.534459]
[http://dx.doi.org/10.1016/j.tips.2014.05.007] [PMID: 24975478]
[http://dx.doi.org/10.1038/nature08638] [PMID: 20054396]
[http://dx.doi.org/10.1517/13543784.2011.570329] [PMID: 21438742]
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0629] [PMID: 25388286]
[http://dx.doi.org/10.1038/s41388-018-0241-0] [PMID: 29643476]
[http://dx.doi.org/10.1016/j.bbamcr.2014.10.022] [PMID: 25447675]
[http://dx.doi.org/10.1016/j.bioorg.2019.103547] [PMID: 31911307]
[http://dx.doi.org/10.1016/j.ejmech.2015.01.061] [PMID: 25659752]
[http://dx.doi.org/10.3390/molecules22020310] [PMID: 28218676]
[http://dx.doi.org/10.1016/j.bmc.2016.06.032] [PMID: 27353887]
[http://dx.doi.org/10.3390/molecules22111870] [PMID: 29088090]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0134] [PMID: 27126994]
[http://dx.doi.org/10.1093/annonc/mdw282] [PMID: 27672108]
[http://dx.doi.org/10.18632/oncotarget.1484] [PMID: 24659719]
[http://dx.doi.org/10.1016/j.bmc.2022.117067] [PMID: 36272186]
[http://dx.doi.org/10.1016/j.bmcl.2007.04.006] [PMID: 17466518]
[http://dx.doi.org/10.1002/jhet.5570450343]
[PMID: 35023010]
[http://dx.doi.org/10.1016/j.bcmd.2006.12.003] [PMID: 17344076]
[http://dx.doi.org/10.1007/s10517-010-1043-8] [PMID: 21165437]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2797] [PMID: 20606037]
[http://dx.doi.org/10.1016/j.ejmech.2019.07.055] [PMID: 31387063]
[http://dx.doi.org/10.3389/fchem.2022.815534] [PMID: 35464202]
[http://dx.doi.org/10.1007/BF03245920]
[http://dx.doi.org/10.1038/nrc.2017.86] [PMID: 29059149]
[http://dx.doi.org/10.1016/j.jmgm.2013.03.001] [PMID: 23567933]
[http://dx.doi.org/10.2174/0929867325666180313110254] [PMID: 29532748]
[http://dx.doi.org/10.1146/annurev.immunol.22.012703.104731] [PMID: 15032592]
[http://dx.doi.org/10.1016/j.ejmech.2020.113040] [PMID: 33316692]
[http://dx.doi.org/10.1155/2014/150845]
[http://dx.doi.org/10.1158/2159-8290.CD-15-0011] [PMID: 25895919]
[http://dx.doi.org/10.1016/j.cell.2011.02.034] [PMID: 21458670]
[http://dx.doi.org/10.1016/j.pharmthera.2019.107450] [PMID: 31836456]
[http://dx.doi.org/10.1073/pnas.93.7.2850] [PMID: 8610130]
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb01054.x] [PMID: 8978690]
[http://dx.doi.org/10.1146/annurev.biochem.73.011303.073723] [PMID: 15189136]
[http://dx.doi.org/10.1126/science.1083430] [PMID: 12791985]
[http://dx.doi.org/10.1016/j.molstruc.2020.129851]
[http://dx.doi.org/10.1016/j.bmcl.2021.128230] [PMID: 34186178]
[http://dx.doi.org/10.1016/j.poly.2020.114503]
[http://dx.doi.org/10.3390/ijms21051665] [PMID: 32121303]
[http://dx.doi.org/10.3390/ijms19102994] [PMID: 30274380]