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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.
{ "@context": "https://schema.org/", "@id": 271194, "@type": "ScholarlyArticle", "creator": [ { "@type": "Person", "affiliation": "Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia", "name": "Wijesinghe, Tharushi P." }, { "@type": "Person", "affiliation": "Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia", "name": "Kaya, Busra" }, { "@type": "Person", "affiliation": "Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia", "name": "Gonzalvez, Miguel A." }, { "@type": "Person", "affiliation": "Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia", "name": "Harmer, Jeffrey R." }, { "@type": "Person", "affiliation": "Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia", "name": "Gholam Azad, Mahan" }, { "@type": "Person", "affiliation": "Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia", "name": "Bernhardt, Paul V." }, { "@type": "Person", "affiliation": "Griffith Univ, Griffith Inst Drug Discovery, Ctr Canc Cell Biol & Drug Discovery, Brisbane, Qld 4111, Australia", "name": "Dharmasivam, Mahendiran" }, { "@type": "Person", "name": "Richardson, Des R." } ], "datePublished": "2023-01-01", "description": "<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>", "headline": "Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series", "identifier": 271194, "image": "https://aperta.ulakbim.gov.tr/static/img/logo/aperta_logo_with_icon.svg", "license": "http://www.opendefinition.org/licenses/cc-by", "name": "Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series", "url": "https://aperta.ulakbim.gov.tr/record/271194" }
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