Inhibitory mechanisms of heterocyclic carboxaldehyde thiosemicabazones for two forms of human ribonucleotide reductase

Zhu, Lijun; Zhou, Bingsen; Chen, Xinhuan; Jiang, H.; Shao, Jimin; Yen, Yun

doi:10.1016/j.bcp.2009.06.103

Cited by 34 publications

(48 citation statements)

References 35 publications

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“…Then the iron(II) complex reacts with oxygen, which leads to the formation of reactive oxygen species (ROS) able to quench the RNR's tyrosyl radical. 22,23,24 However, quite recently it was found that quenching of the tyrosyl radical is not oxygen dependent, suggesting that it might be reduced directly by the Fe(II)-Triapine complex without involvement of ROS. 25 A second known target for HCTs is topoisomerase IIα (Topo IIα) an enzyme which controls the DNA topology during cell division by inducing temporary double strand breaks.…”

Section: Introductionmentioning

confidence: 99%

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

et al. 2014

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The nickel(II), copper(II) and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H 2 L 1 ) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazonehave been synthesized and characterized by elemental analysis, one-and two-dimensional 1 H and 13 C NMR spectroscopy, CD, UV−vis and ESI mass spectrometry. Compounds 13, 6 and 7 have been also studied by single crystal X-ray diffraction. Magnetic properties and solid state high-field EPR spectra of 2 over the range 50420 GHz were investigated. The complex formation processes of L-Pro-FTSC with nickel(II) and zinc(II) have been studied in aqueous solution due to the excellent water solubility of the complexes via pH-potentiometry, UV−vis and 1 H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.3

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Section: Introductionmentioning

confidence: 99%

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

et al. 2014

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“…In a second model 3-AP is proposed to chelate iron from the intracellular iron pool(s) (18,20) (30). A third model, which is the one currently favored in the literature, is that Fe(III)-(3-AP) is reduced to Fe(II)-(3-AP) by endogenous reductants, which in turn reacts with O 2 and produces ROS that inactivate RNR (21,(27)(28)(29). A direct interaction of Y⅐ with O 2 .…”

mentioning

confidence: 99%

“…In one model free 3-AP is proposed to chelate the Fe(III) directly from the [(Fe (14,28,29), resulting in RNR inactivation. In a second model 3-AP is proposed to chelate iron from the intracellular iron pool(s) (18,20) (30).…”

mentioning

confidence: 99%

Mechanistic Studies of Semicarbazone Triapine Targeting Human Ribonucleotide Reductase in Vitro and in Mammalian Cells

Aye

Long

Stubbe

2012

Journal of Biological Chemistry

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Triapine® (3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP)) is a drug in Phase II trials. One of its established cellular targets is the β2 subunit of ribonucleotide reductase that requires a diferric-tyrosyl-radical [(FeIII2-Y·)(FeIII2)] cofactor for de novo DNA biosynthesis. Several mechanisms for 3-AP inhibition of β2 have been proposed; one involves direct iron chelation from β2, whereas a second involves Y· destruction by reactive oxygen species formed in situ in the presence of O2 and reductant by Fe(II)-(3-AP). Inactivation of β2 can thus arise from cofactor destruction by loss of iron or Y·. In vitro kinetic data on the rates of 55Fe and Y· loss from [(55FeIII2-Y·)(55FeIII2)]-β2 under aerobic and anaerobic conditions reveal that Y· loss alone is sufficient for rapid β2 inactivation. OxyblotTM and mass spectrometric analyses of trypsin-digested inhibited β2, and lack of Y· loss from H2O2 and O2̇̄ treatment together preclude reactive oxygen species involvement in Y· loss. Three mammalian cell lines treated with 5 μm 3-AP reveal Y· loss and β2 inactivation within 30-min of 3-AP-exposure, analyzed by whole-cell EPR and lysate assays, respectively. Selective degradation of apo- over [(FeIII2-Y·)(FeIII2)]-β2 in lysates, similar iron-content in β2 immunoprecipitated from 3-AP-treated and untreated [55Fe]-prelabeled cells, and prolonged (12 h) stability of the inhibited β2 are most consistent with Y· loss being the predominant mode of inhibition, with β2 remaining iron-loaded and stable. A model consistent with in vitro and cell-based biochemical studies is presented in which Fe(II)-(3-AP), which can be cycled with reductant, directly reduces Y· of the [(FeIII2-Y·)(FeIII2)] cofactor of β2.

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“…Over the years thousands of cisplatin analogues have been 15 synthesized varying the nature of the leaving groups, the metal or the carrier ligand, yet only a handful of them have been approved for clinical use. The limited success in metal-based anticancer research appears to be caused by the relative lack in structural diversity encountered in the reported compounds.…”

Section: -4mentioning

confidence: 99%

Chemistry, antiproliferative activity and low nephrotoxicity of 3,5-diacetyl-1,2,4-triazol bis(4N-thiosemicarbazone) ligands and their platinum(ii) complexes

2010

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El acceso a la versión del editor puede requerir la suscripción del recurso Access to the published version may require subscription PAPER www.rsc.org/dalton | Dalton Transactions Chemistry, antiproliferative activity and low nephrotoxicity of The preparation and characterization of 3,5-diacetyl-1,2,4-triazol bis(4,4-dimethyl thiosemicarbazone) ligand, H 3 L 1 , and its dinuclear platinum complex [Pt(m-HL 1 )] 2 is described. The crystal and molecular structure of the platinum complex has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized together with the analogous monosubstituted ligand 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H 5 L 2 ) and its dinuclear platinum(II) complex [Pt(m-H 3 L 2 )] 2 have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H 3 L 1 and [Pt(m-H 3 L 2 )] 2 since they not only circumvent cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. Subsequent nephrotoxic study, in LLC-PK1 cells, show that the four compounds investigated exhibit very low nephrotoxicity with respect to cisplatin.

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Inhibitory mechanisms of heterocyclic carboxaldehyde thiosemicabazones for two forms of human ribonucleotide reductase

Cited by 34 publications

References 35 publications

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

Mechanistic Studies of Semicarbazone Triapine Targeting Human Ribonucleotide Reductase in Vitro and in Mammalian Cells

Chemistry, antiproliferative activity and low nephrotoxicity of 3,5-diacetyl-1,2,4-triazol bis(4N-thiosemicarbazone) ligands and their platinum(ii) complexes

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