1 Ocak 2023 Dergi makalesi Açık Erişim

Wijesinghe, Tharushi P.; Kaya, Busra; Gonzalvez, Miguel A.; Harmer, Jeffrey R.; Gholam Azad, Mahan; Bernhardt, Paul V.; Dharmasivam, Mahendiran; Richardson, Des R.

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{
  "DOI": "10.1021/acs.jmedchem.3c01612", 
  "abstract": "<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>", 
  "author": [
    {
      "family": "Wijesinghe", 
      "given": " Tharushi P."
    }, 
    {
      "family": "Kaya", 
      "given": " Busra"
    }, 
    {
      "family": "Gonzalvez", 
      "given": " Miguel A."
    }, 
    {
      "family": "Harmer", 
      "given": " Jeffrey R."
    }, 
    {
      "family": "Gholam Azad", 
      "given": " Mahan"
    }, 
    {
      "family": "Bernhardt", 
      "given": " Paul V."
    }, 
    {
      "family": "Dharmasivam", 
      "given": " Mahendiran"
    }, 
    {
      "family": "Richardson", 
      "given": " Des R."
    }
  ], 
  "container_title": "JOURNAL OF MEDICINAL CHEMISTRY", 
  "id": "271194", 
  "issue": "22", 
  "issued": {
    "date-parts": [
      [
        2023, 
        1, 
        1
      ]
    ]
  }, 
  "page": "24", 
  "title": "Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series", 
  "type": "article-journal", 
  "volume": "66"
}