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Wijesinghe, Tharushi P.; Kaya, Busra; Gonzalvez, Miguel A.; Harmer, Jeffrey R.; Gholam Azad, Mahan; Bernhardt, Paul V.; Dharmasivam, Mahendiran; Richardson, Des R.
<?xml version='1.0' encoding='UTF-8'?> <record xmlns="http://www.loc.gov/MARC21/slim"> <leader>00000nam##2200000uu#4500</leader> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Kaya, Busra</subfield> <subfield code="u">Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Gonzalvez, Miguel A.</subfield> <subfield code="u">Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Harmer, Jeffrey R.</subfield> <subfield code="u">Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Gholam Azad, Mahan</subfield> <subfield code="u">Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Bernhardt, Paul V.</subfield> <subfield code="u">Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Dharmasivam, Mahendiran</subfield> <subfield code="u">Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Richardson, Des R.</subfield> </datafield> <datafield tag="909" ind1="C" ind2="4"> <subfield code="p">JOURNAL OF MEDICINAL CHEMISTRY</subfield> <subfield code="v">66</subfield> <subfield code="n">22</subfield> <subfield code="c">24</subfield> </datafield> <datafield tag="980" ind1=" " ind2=" "> <subfield code="a">user-tubitak-destekli-proje-yayinlari</subfield> </datafield> <datafield tag="540" ind1=" " ind2=" "> <subfield code="a">Creative Commons Attribution</subfield> <subfield code="u">http://www.opendefinition.org/licenses/cc-by</subfield> </datafield> <datafield tag="024" ind1=" " ind2=" "> <subfield code="a">10.1021/acs.jmedchem.3c01612</subfield> <subfield code="2">doi</subfield> </datafield> <datafield tag="245" ind1=" " ind2=" "> <subfield code="a">Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series</subfield> </datafield> <datafield tag="100" ind1=" " ind2=" "> <subfield code="a">Wijesinghe, Tharushi P.</subfield> <subfield code="u">Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia</subfield> </datafield> <datafield tag="909" ind1="C" ind2="O"> <subfield code="o">oai:aperta.ulakbim.gov.tr:271194</subfield> <subfield code="p">user-tubitak-destekli-proje-yayinlari</subfield> </datafield> <datafield tag="650" ind1="1" ind2="7"> <subfield code="2">opendefinition.org</subfield> <subfield code="a">cc-by</subfield> </datafield> <datafield tag="260" ind1=" " ind2=" "> <subfield code="c">2023-01-01</subfield> </datafield> <datafield tag="856" ind1="4" ind2=" "> <subfield code="u">https://aperta.ulakbim.gov.trrecord/271194/files/bib-39813977-68c4-4f4d-a289-f50bad3ec3b5.txt</subfield> <subfield code="z">md5:79d25c5d117b1993789e4a60257aceb1</subfield> <subfield code="s">304</subfield> </datafield> <datafield tag="542" ind1=" " ind2=" "> <subfield code="l">open</subfield> </datafield> <controlfield tag="005">20240607163044.0</controlfield> <controlfield tag="001">271194</controlfield> <datafield tag="980" ind1=" " ind2=" "> <subfield code="a">publication</subfield> <subfield code="b">article</subfield> </datafield> <datafield tag="520" ind1=" " ind2=" "> <subfield code="a"><p>The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe-(III), Cu-(II), and Zn-(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009-0.066 mu M), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu-(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe-(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe-(III) complexes to the heme plane and its oxidation. The 1:1 Cu-(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.</p></subfield> </datafield> </record>
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