Abstract
Background: The cancer is still a major cause of death worldwide. Among different targets to design anticancer agents, caspase-3 is an important target as its cleavage and activation lead to apoptosis and finally, cancer cell death. Apart from some naturally occurring molecules, many small molecules have been reported as caspase-3 activators.
Objectives: In view of the above, the objective has been to review the published work on small molecules reported as caspase-3 activators and their anticancer activity to get some novel lead molecules for designing novel molecules of improved cancer therapeutic.
Methods: Literature search has been carried out using different search engines like google, Elsevier, Science direct, RSC, etc. for the publications of small molecules as caspase-3 activators inducing apoptosis in cancer cells.
Results: In this review, the small molecules showing caspase-3 cleavage and activation have been discussed under different broad chemical classes so as to provide some insight into the structural features responsible for caspase-3 activation leading to anticancer activity. The review also encompasses the established drugs, novel organometallics showing caspase-3 activation and anticancer activity.
Conclusion: A large number of small molecules including some established drugs and organometallics have shown cleavage and activation of caspase-3 leading to apoptosis and anticancer activity. Many reported potent molecules of different chemical classes may be useful as lead molecules for optimization of anticancer activity as well as they may provide an insight of structural features which may be useful in designing novel caspase-3 activators as anticancer agents for drug development.
Graphical Abstract
[http://dx.doi.org/10.1038/38225] [PMID: 9296491]
[http://dx.doi.org/10.1126/science.274.5293.1664] [PMID: 8939848]
[http://dx.doi.org/10.1126/science.1125951] [PMID: 16728632]
[http://dx.doi.org/10.2165/00003495-200767170-00013] [PMID: 18034597]
[http://dx.doi.org/10.2174/157489206778776925] [PMID: 18221049]
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4719] [PMID: 18316545]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2854] [PMID: 17363519]
[http://dx.doi.org/10.1146/annurev.pharmtox.41.1.367] [PMID: 11264462]
[http://dx.doi.org/10.1016/0022-1910(65)90099-5] [PMID: 14287218]
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[http://dx.doi.org/10.1038/bjc.1972.33] [PMID: 4561027]
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[http://dx.doi.org/10.1590/1519-6984.228437] [PMID: 33111928]
[http://dx.doi.org/10.1016/j.semcancer.2015.03.008]
[http://dx.doi.org/10.1146/annurev.biochem.68.1.383] [PMID: 10872455]
[http://dx.doi.org/10.1515/hsz-2014-0253] [PMID: 25389992]
[http://dx.doi.org/10.1046/j.1523-1747.2002.19532.x] [PMID: 12445205]
[http://dx.doi.org/10.1111/cbdd.13860] [PMID: 33963665]
[http://dx.doi.org/10.1074/mcp.O112.024372] [PMID: 23264352]
[http://dx.doi.org/10.1126/science.278.5336.294] [PMID: 9323209]
[http://dx.doi.org/10.1186/1742-4682-5-26] [PMID: 19077196]
[http://dx.doi.org/10.1038/nri911] [PMID: 12360212]
[http://dx.doi.org/10.1016/S0952-7915(03)00108-0] [PMID: 14499264]
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a011623] [PMID: 9374030]
[http://dx.doi.org/10.1074/jbc.272.30.18530] [PMID: 9228015]
[http://dx.doi.org/10.1042/bj3500563] [PMID: 10947972]
[http://dx.doi.org/10.1038/sj.cdd.4400963] [PMID: 11803369]
[http://dx.doi.org/10.1016/S0092-8674(00)80748-5] [PMID: 10319819]
[http://dx.doi.org/10.1172/JCI26252] [PMID: 16200200]
[http://dx.doi.org/10.1111/j.1742-4658.2007.05994.x]
[http://dx.doi.org/10.1074/jbc.272.29.17907] [PMID: 9218414]
[http://dx.doi.org/10.1038/cdd.2017.44] [PMID: 28498362]
[http://dx.doi.org/10.2174/138955708785909899] [PMID: 18855730]
[http://dx.doi.org/10.1126/science.278.5345.1966] [PMID: 9395403]
[http://dx.doi.org/10.1073/pnas.93.16.8395] [PMID: 8710882]
[http://dx.doi.org/10.1002/bab.2233] [PMID: 34342377]
[http://dx.doi.org/10.1002/cbdv.201800322] [PMID: 30054973]
[http://dx.doi.org/10.1016/j.bioorg.2018.07.008] [PMID: 30014921]
[http://dx.doi.org/10.1038/s41598-022-06887-0] [PMID: 35190616]
[http://dx.doi.org/10.1080/14756366.2018.1555536] [PMID: 30734614]
[http://dx.doi.org/10.1080/00397911.2021.1945105]
[http://dx.doi.org/10.1080/14756366.2021.1901089] [PMID: 33896327]
[http://dx.doi.org/10.4161/cbt.11.5.14529] [PMID: 21263218]
[http://dx.doi.org/10.1016/j.ejmech.2019.02.051]
[http://dx.doi.org/10.3390/molecules17066179] [PMID: 22634834]
[PMID: 25313764]
[http://dx.doi.org/10.1021/jm049640t] [PMID: 15566300]
[http://dx.doi.org/10.1021/jm070216c] [PMID: 17497765]
[http://dx.doi.org/10.1080/14756366.2018.1476503] [PMID: 29923425]
[http://dx.doi.org/10.1080/08923973.2016.1203928] [PMID: 27324722]
[http://dx.doi.org/10.1179/joc.2007.19.4.428] [PMID: 17855188]
[http://dx.doi.org/10.1016/j.bmc.2004.04.017] [PMID: 15186849]
[http://dx.doi.org/10.1080/15384047.2015.1071731] [PMID: 26192233]
[http://dx.doi.org/10.1080/14756366.2017.1421181] [PMID: 29560733]
[http://dx.doi.org/10.1038/srep33204] [PMID: 27625151]
[http://dx.doi.org/10.1371/journal.pone.0129874] [PMID: 26134408]
[http://dx.doi.org/10.1080/26895293.2022.2052191]
[http://dx.doi.org/10.1182/blood.V93.7.2342] [PMID: 10090945]
[http://dx.doi.org/10.1080/10715760000300511] [PMID: 10798716]
[http://dx.doi.org/10.1016/j.biopha.2017.08.110] [PMID: 28888209]
[http://dx.doi.org/10.1016/j.bmcl.2020.127438] [PMID: 32736079]
[http://dx.doi.org/10.1021/jm050292k] [PMID: 16078840]
[http://dx.doi.org/10.3390/chemistry3010027]
[http://dx.doi.org/10.1016/j.arabjc.2014.05.034]
[http://dx.doi.org/10.1038/17409] [PMID: 10028971]
[http://dx.doi.org/10.1023/A:1026758429238] [PMID: 11201051]
[http://dx.doi.org/10.1080/14756366.2019.1639695] [PMID: 31307242]
[http://dx.doi.org/10.1038/nchembio814] [PMID: 16936720]
[http://dx.doi.org/10.1111/jcmm.12566] [PMID: 25754465]
[http://dx.doi.org/10.1080/15384047.2016.1210733] [PMID: 27415751]
[http://dx.doi.org/10.1080/14756366.2019.1642883] [PMID: 31322015]
[PMID: 29061816]
[http://dx.doi.org/10.3109/14756366.2012.724682] [PMID: 23020635]
[http://dx.doi.org/10.1126/science.1076807] [PMID: 12522243]
[http://dx.doi.org/10.1021/jm0205200] [PMID: 12773051]
[http://dx.doi.org/10.3390/molecules23061459] [PMID: 29914120]
[http://dx.doi.org/10.1080/14756366.2018.1547286] [PMID: 30722708]
[http://dx.doi.org/10.1080/14756366.2018.1564046] [PMID: 30688116]
[http://dx.doi.org/10.1080/14756366.2022.2051022] [PMID: 35345960]
[http://dx.doi.org/10.1080/14756366.2020.1740692] [PMID: 32223461]
[http://dx.doi.org/10.1080/14756366.2019.1612889] [PMID: 31117890]
[http://dx.doi.org/10.1016/j.bmc.2006.08.002] [PMID: 16919962]
[http://dx.doi.org/10.1016/j.bmcl.2009.02.074] [PMID: 19285392]
[http://dx.doi.org/10.1016/j.bmcl.2009.04.145] [PMID: 19464890]
[PMID: 11016650]
[http://dx.doi.org/10.2174/1871520618666180409155520]
[http://dx.doi.org/10.1021/jm8003653] [PMID: 18651728]
[http://dx.doi.org/10.1021/jm801315b] [PMID: 19296653]
[http://dx.doi.org/10.1016/j.bmcl.2010.01.155] [PMID: 20188546]
[http://dx.doi.org/10.1016/j.bmc.2009.02.029] [PMID: 19282188]
[http://dx.doi.org/10.2174/1573409911666150701103342] [PMID: 26126610]
[http://dx.doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-1.12414] [PMID: 30932417]
[http://dx.doi.org/10.1155/2014/212096] [PMID: 25548779]
[http://dx.doi.org/10.4155/fmc-2017-0284] [PMID: 29749767]
[http://dx.doi.org/10.1371/journal.pone.0142678] [PMID: 26599982]
[http://dx.doi.org/10.1080/14756366.2019.1605364] [PMID: 31072147]
[http://dx.doi.org/10.1080/1062936X.2020.1827030] [PMID: 33100034]
[http://dx.doi.org/10.1080/14756366.2020.1839446] [PMID: 33161799]
[http://dx.doi.org/10.1016/j.bioorg.2019.102938] [PMID: 31028992]
[http://dx.doi.org/10.3906/kim-1907-71]
[http://dx.doi.org/10.1016/j.ejmech.2018.03.026] [PMID: 29547830]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-2689] [PMID: 19451594]
[PMID: 25075032]
[http://dx.doi.org/10.2174/18715206113136660369] [PMID: 24164046]
[http://dx.doi.org/10.3390/ijms19061625] [PMID: 29857489]
[http://dx.doi.org/10.1080/14756366.2021.1915303] [PMID: 34056992]
[http://dx.doi.org/10.1080/14756366.2021.1956488] [PMID: 34340610]
[http://dx.doi.org/10.1080/14756366.2021.1945591] [PMID: 34325596]
[http://dx.doi.org/10.1038/cgt.2013.29] [PMID: 23703473]
[http://dx.doi.org/10.4161/cc.7.1.5103] [PMID: 18196976]
[http://dx.doi.org/10.1002/2211-5463.12419] [PMID: 29744295]
[http://dx.doi.org/10.1080/07391102.2019.1654924] [PMID: 31411114]
[http://dx.doi.org/10.1016/j.bmc.2013.09.047] [PMID: 24148834]
[PMID: 12566301]
[http://dx.doi.org/10.1016/j.bmcl.2007.05.098] [PMID: 17562361]
[http://dx.doi.org/10.3109/14756366.2013.763253] [PMID: 23391122]
[http://dx.doi.org/10.1038/s41598-019-47177-6]
[http://dx.doi.org/10.1002/ardp.201400230] [PMID: 25230149]
[http://dx.doi.org/10.1016/j.ejmech.2011.06.031] [PMID: 21775028]
[http://dx.doi.org/10.1002/cmdc.201100511] [PMID: 22241597]
[http://dx.doi.org/10.3892/ol.2017.5995] [PMID: 28599449]
[http://dx.doi.org/10.3892/ol.2018.9131] [PMID: 30127955]
[http://dx.doi.org/10.1186/1471-2407-13-233] [PMID: 23663432]
[http://dx.doi.org/10.1016/j.bcp.2011.08.017] [PMID: 21889928]
[http://dx.doi.org/10.1016/j.biopha.2011.02.016] [PMID: 21723078]
[PMID: 11085519]
[http://dx.doi.org/10.3389/fphar.2021.670081] [PMID: 34305590]
[http://dx.doi.org/10.1080/00958972.2019.1575964]
[http://dx.doi.org/10.1038/srep46056] [PMID: 28436418]
[http://dx.doi.org/10.1038/srep09157] [PMID: 25778692]
[http://dx.doi.org/10.1080/23312025.2016.1154282]
[http://dx.doi.org/10.1038/sj.bjc.6604021] [PMID: 17923871]
[http://dx.doi.org/10.1080/00958972.2022.2045586]