Abstract
Phthalazinones are important nitrogen-rich heterocyclic compounds which have been a topic of considerable medicinal interest because of their diversified pharmacological activities. This versatile scaffold forms a common structural feature for many bioactive compounds, which leads to the design and development of novel anticancer drugs with fruitful results. The current review article discusses the progressive development of novel phthalazinone analogues that are targets for various receptors such as PARP, EGFR, VEGFR-2, Aurora kinase, Proteasome, Hedgehog pathway, DNA topoisomerase and P-glycoprotein. It describes mechanistic insights into the anticancer properties of phthalazinone derivatives and also highlights various simple and economical techniques for the synthesis of phthalazinones.
Keywords: Cancer, phthalazinone, PARP inhibitor, VEGFR and EGFR inhibitors, aurora kinase inhibitors, proteasome inhibitors, hedgehog pathway inhibitors, DNA topoisomerases inhibitors, P-glycoprotein inhibitors.
Graphical Abstract
[http://dx.doi.org/10.1016/j.ejmech.2014.03.018] [PMID: 24685980]
[http://dx.doi.org/10.3389/fonc.2013.00257] [PMID: 24137565]
[http://dx.doi.org/10.1016/j.ctrv.2014.11.003] [PMID: 25498841]
[http://dx.doi.org/10.1248/bpb.b15-00656] [PMID: 26830483]
[http://dx.doi.org/10.1016/j.bmc.2019.07.050] [PMID: 31401008]
[http://dx.doi.org/10.1016/j.ejmech.2018.10.047] [PMID: 30388463]
[http://dx.doi.org/10.1002/chem.201601499] [PMID: 27440529]
[http://dx.doi.org/10.1021/jf061976j] [PMID: 17117801]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3001] [PMID: 20935223]
[http://dx.doi.org/10.1007/s10637-013-9978-z] [PMID: 23700288]
[http://dx.doi.org/10.1517/13543776.15.6.647] [PMID: 20141503]
[http://dx.doi.org/10.1021/jm8001263] [PMID: 18800822]
[http://dx.doi.org/10.1517/13543776.2013.768615] [PMID: 23379721]
[http://dx.doi.org/10.1016/j.bmcl.2005.10.081] [PMID: 16290932]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-2079] [PMID: 19147766]
[http://dx.doi.org/10.1016/j.bmcl.2015.10.079] [PMID: 26546219]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01498] [PMID: 26652717]
[http://dx.doi.org/10.1080/00498254.2018.1546916] [PMID: 30488748]
[http://dx.doi.org/10.1016/j.canlet.2016.11.010] [PMID: 27847302]
[http://dx.doi.org/10.1016/j.bmcl.2016.05.009] [PMID: 27180012]
[http://dx.doi.org/10.1021/jm970815r] [PMID: 9719589]
[http://dx.doi.org/10.1021/jm101346r] [PMID: 21128645]
[http://dx.doi.org/10.1021/jo00118a005]
[http://dx.doi.org/10.1016/j.ejmech.2004.09.005] [PMID: 15571871]
[http://dx.doi.org/10.1016/j.bmcl.2009.07.075] [PMID: 19646868]
[http://dx.doi.org/10.1039/C6RA03841G]
[http://dx.doi.org/10.1002/chem.201302495] [PMID: 24038329]
[http://dx.doi.org/10.1021/jm001002x] [PMID: 10956193]
[http://dx.doi.org/10.1016/0040-4039(96)00544-8]
[http://dx.doi.org/10.1016/j.ejmech.2014.11.043] [PMID: 25482553]
[http://dx.doi.org/10.1021/jm010837k] [PMID: 11472205]
[http://dx.doi.org/10.1016/j.ejmech.2009.10.028] [PMID: 20149488]
[http://dx.doi.org/10.1021/jm00394a006] [PMID: 2822927]
[http://dx.doi.org/10.1002/pola.21880]
[http://dx.doi.org/10.1016/S0040-4020(01)91312-2]
[http://dx.doi.org/10.1016/0040-4039(95)00202-N]
[http://dx.doi.org/10.1021/acs.oprd.5b00135]
[http://dx.doi.org/10.1021/jo3000628] [PMID: 22458369]
[http://dx.doi.org/10.1002/jhet.5570310228]
[http://dx.doi.org/10.1055/s-2001-10804]
[http://dx.doi.org/10.1081/SCC-120030319]
[http://dx.doi.org/10.1016/0040-4020(95)01109-9]
[http://dx.doi.org/10.1080/00397911.2015.1025282]
[http://dx.doi.org/10.1080/00397911.2011.622847]
[http://dx.doi.org/10.1016/j.tetlet.2014.12.121]
[http://dx.doi.org/10.1021/jm00105a018] [PMID: 1899452]
[http://dx.doi.org/10.1016/j.ejmech.2016.02.023] [PMID: 26922232]
[http://dx.doi.org/10.1002/jps.2600690140] [PMID: 7354426]
[http://dx.doi.org/10.1016/S0960-894X(00)00587-4] [PMID: 11140727]
[http://dx.doi.org/10.1039/p19770002037]
[http://dx.doi.org/10.1039/C5RA03390J]
[http://dx.doi.org/10.1021/jo034510y] [PMID: 12919054]
[http://dx.doi.org/10.1016/j.bmcl.2013.02.027] [PMID: 23453843]
[http://dx.doi.org/10.1021/acs.joc.5b00142] [PMID: 25763805]
[http://dx.doi.org/10.1021/acs.joc.5b02652] [PMID: 26795884]
[http://dx.doi.org/10.2741/2909] [PMID: 17981777]
[http://dx.doi.org/10.1038/nrc2812] [PMID: 20200537]
[http://dx.doi.org/10.2174/2212697X01666140128002849]
[http://dx.doi.org/10.1074/jbc.274.25.17860] [PMID: 10364231]
[http://dx.doi.org/10.1038/nrm1963] [PMID: 16829982]
[http://dx.doi.org/10.1200/JCO.2014.58.8848] [PMID: 25779564]
[http://dx.doi.org/10.1016/j.bioorg.2018.01.034] [PMID: 29453076]
[http://dx.doi.org/10.1016/j.ddmod.2012.01.004]
[http://dx.doi.org/10.1016/j.ejmech.2017.06.053] [PMID: 28692916]
[http://dx.doi.org/10.1007/s00280-018-3653-1] [PMID: 30046848]
[http://dx.doi.org/10.1016/j.bmcl.2014.07.001] [PMID: 25086680]
[http://dx.doi.org/10.1016/j.bmcl.2005.03.026] [PMID: 15837300]
[http://dx.doi.org/10.3390/cancers3021513] [PMID: 24212772]
[http://dx.doi.org/10.1200/JCO.2002.10.088] [PMID: 12409337]
[http://dx.doi.org/10.1038/s41598-018-30804-z] [PMID: 30127519]
[http://dx.doi.org/10.1016/j.ejmech.2015.10.053] [PMID: 26590508]
[http://dx.doi.org/10.1016/j.bioorg.2018.12.039] [PMID: 30654221]
[http://dx.doi.org/10.1016/j.ejmech.2016.07.049] [PMID: 27484508]
[http://dx.doi.org/10.1016/j.ejmech.2016.02.029] [PMID: 26922228]
[http://dx.doi.org/10.1016/j.bmc.2008.11.049] [PMID: 19101155]
[http://dx.doi.org/10.1021/jm9909443] [PMID: 10882357]
[http://dx.doi.org/10.1016/j.pharmthera.2006.02.006] [PMID: 16603252]
[http://dx.doi.org/10.1038/nrm1245] [PMID: 14625535]
[http://dx.doi.org/10.1023/A:1023789416385] [PMID: 12884918]
[PMID: 18662747]
[http://dx.doi.org/10.1016/0092-8674(95)90374-7] [PMID: 7720077]
[http://dx.doi.org/10.1038/35048096] [PMID: 11413462]
[http://dx.doi.org/10.1016/j.ejmech.2017.08.045] [PMID: 28918096]
[http://dx.doi.org/10.1016/j.bmc.2018.04.048] [PMID: 29705376]
[http://dx.doi.org/10.2174/1381612811319220012] [PMID: 23181572]
[http://dx.doi.org/10.1021/cr0502504] [PMID: 17316053]
[http://dx.doi.org/10.1016/j.bmcl.2016.04.067] [PMID: 27158142]
[http://dx.doi.org/10.1002/med.21555] [PMID: 30484872]
[http://dx.doi.org/10.1038/415436a] [PMID: 11807556]
[http://dx.doi.org/10.1016/j.bmc.2010.07.038] [PMID: 20708941]
[http://dx.doi.org/10.1056/NEJMoa0902903] [PMID: 19726761]
[http://dx.doi.org/10.1056/NEJMoa0905360] [PMID: 19726763]
[http://dx.doi.org/10.1016/j.tips.2009.03.007] [PMID: 19443052]
[http://dx.doi.org/10.1021/jm900309j] [PMID: 19469545]
[http://dx.doi.org/10.1016/j.bmcl.2010.04.110] [PMID: 20493695]
[http://dx.doi.org/10.1126/science.279.5356.1534] [PMID: 9488652]
[http://dx.doi.org/10.1016/S0079-6603(08)60891-0] [PMID: 9594573]
[http://dx.doi.org/10.1038/nrc1977] [PMID: 16990856]
[http://dx.doi.org/10.1039/C9RA09016A]
[http://dx.doi.org/10.1016/j.ejmech.2010.05.048] [PMID: 20638158]
[http://dx.doi.org/10.1098/rstb.2008.0125] [PMID: 18957379]
[http://dx.doi.org/10.1152/physrev.00037.2005] [PMID: 17015488]
[http://dx.doi.org/10.1016/j.drup.2016.03.001] [PMID: 27180306]
[http://dx.doi.org/10.2174/092986712800167392] [PMID: 22257057]
[PMID: 7214365]
[http://dx.doi.org/10.1016/S0928-0987(00)00114-7] [PMID: 11033070]
[http://dx.doi.org/10.1016/0959-8049(96)00091-3] [PMID: 8763349]
[http://dx.doi.org/10.1016/j.bioorg.2019.01.039] [PMID: 30710850]