5397-03-5Relevant articles and documents
Synthesis, characterization, antiparasitic and cytotoxic evaluation of thioureas conjugated to polyamine scaffolds
Stringer, Tameryn,Taylor, Dale,De Kock, Carmen,Guzgay, Hajira,Au, Aaron,An, Seung Hwan,Sanchez, Benjamin,O'Connor, Raquel,Patel, Neal,Land, Kirkwood M.,Smith, Peter J.,Hendricks, Denver T.,Egan, Timothy J.,Smith, Gregory S.
, p. 90 - 98 (2013)
A series of mono- and multimeric 4-amino-7-chloroquinoline and ferrocenyl thioureas have been prepared by the reaction of a 7-chloroquinoline methyl ester and a ferrocenylimine methyl ester with various amines. These compounds were characterized using standard spectroscopic and analytical techniques. The compounds were evaluated against the NF54 (CQ-sensitive) and Dd2 (CQ-resistant) strains of Plasmodiumfalciparum. The quinoline compounds show enhanced activity compared to the ferrocene compounds against this parasite. Compound 5 displays the most promising activity against the NF54 strain. Compounds 5 and 6 are effective at inhibiting β-hematin formation perhaps due to an increased number of quinoline moieties. The trimeric (12) and tetrameric (13) ferrocenyl compounds also inhibit β-hematin formation, albeit to a lesser degree compared to the quinoline thioureas. The compounds were also screened against the G3 strain of Trichomonasvaginalis and here the ferrocene-containing compounds show a slightly higher parasite growth inhibition compared to the quinoline thioureas. The quinoline compounds were also found to be more cytotoxic compared to the ferrocenyl compounds. Compound 6 displays good cytotoxicity against WHCO1 oesophageal cancer cells.
Coordinated dissociative proton transfers of external proton and thiocarbamide hydrogen: MS experimental and theoretical studies on the fragmentation of protonated S-methyl benzenylmethylenehydrazine dithiocarboxylate in gas phase
Jiang, Kezhi,Bian, Gaofeng,Hu, Nan,Pan, Yuanjiang,Lai, Guoqiao
, p. 17 - 23 (2010)
The dissociation chemistry of the protonated S-methyl benzenylmethylenehydrazine dithiocarboxylate, PhCH{double bond, long}N{single bond}NHC({double bond, long}S)SCH3, has been investigated by collision-induced dissociation (CID) mass spectrometry experiments in combination with density functional theory (DFT) calculations. Eliminations of H2S, CH3SH and (NSC)SCH3 were the three fragmentation reactions observed in the tandem mass spectra, witnessed by the MS/MS analysis of native 34S-isotopic ion and the D-labeling CID-MS experiment. Of the three fragmentations, both the added proton and the internal thiocarbamide hydrogen shift to the fragment ion (m/z 106) in the dissociation of losing (NSC)SCH3, while both of them shift to the neutral fragment H2S to generate the minor product ion at m/z 177. In the case of the feasible fragmentation process of CH3SH elimination, one of the proton/the thiocarbamide hydrogen migrates to the fragment ion at m/z 163, and the other migrates to the neutral specie. Calculated results show that thiocarbamide sulfur (S5) is the most thermodynamically favored position for protonation. The mechanisms of these reactions were postulated according to the theoretical results, and the reaction energy profiles were also constructed. These results indicated that fragmentation of the protonated molecule was viewed as a result of the coordinated migration of both the external proton and the thiocarbamide hydrogen.
Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells
Shimada, Kenichi,Reznik, Eduard,Stokes, Michael E.,Krishnamoorthy, Lakshmi,Bos, Pieter H.,Song, Yuyu,Quartararo, Christine E.,Pagano, Nen C.,Carpizo, Darren R.,deCarvalho, Ana C.,Lo, Donald C.,Stockwell, Brent R.
, p. 585 - 7,594 (2018)
Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas. Shimada et al. report that the compound NSC319726 arrests glioblastoma-patient-derived cells at picomolar concentrations. The compound binds to copper, generates ROS using ambient oxygen, and depletes nucleotide pools. This represents a new strategy for potently blocking the growth of glioblastoma.
Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53
Gilleran, John A.,Yu, Xin,Blayney, Alan J.,Bencivenga, Anthony F.,Na, Bing,Augeri, David J.,Blanden, Adam R.,Kimball, S. David,Loh, Stewart N.,Roberge, Jacques Y.,Carpizo, Darren R.
, p. 2024 - 2045 (2021/02/16)
We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.
PHARMACEUTICAL COMPOUNDS AND THERAPEUTIC METHODS
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Page/Page column 9-10, (2020/11/03)
The invention provides a complex comprising Zn2+ and a compound of formula (I): or a deuterated analog thereof, or an ion or poly-ion thereof, or a salt thereof that is useful for treating cancer, as well as compositions and kits comprising such complexes.
The role of methyl and benzyl substituted dithiocarbazate of 2-acetyl pyridine for the formation of bridged dimeric and unbridged monomeric copper(II) complexes and catecholase mimetic activity of the complexes
Santra, Ananyakumari,Brandao, Paula,Mondal, Gopinath,Bera, Pradip,Jana, Abhimanyu,Bhattacharyya, Indranil,Pramanik, Chandana,Bera, Pulakesh
, (2019/12/26)
Monomeric [Cu(L1)Cl] (1) and dimeric [Cu(L2)Cl]2 (2) copper(II) complexes, where HL1 = methyl-2-(1-(pyridine-2-yl)ethylidene)-hydrazine-1-carbodithioate and HL2 = benzyl-2-(1-(pyridine-2-yl)ethylidene)hydrazine-1-carbodithioate, have been synthesized and characterized by X-ray crystallography, TGA and spectral methods. Complex 1 crystallizes in a space group P21/n and adopts a square planar environment surrounding the Cu ion, and complex 2 is a triclinic crystal system with space group Pī. Complex 2 is a centrosymmetric dimer where each copper atom forms two chloro bridges and completes five coordination with the tridentate NNS donor. Density functional calculations demonstrate that chloro-unbridged structure of 1 is favored by London dispersion between its layers. It is noticed that the layers are usually packed closely in the solid phase, such attractive interactions are sterically hindered between the layers of 2. Due to the presence of large phenyl group that extend from one layer to the other, the layers cannot slide on top of each other. This leads to the chloro-bridged structure of 2 stabilized by electrostatic interactions between Cu and Cl atoms located at different layers. Both complexes exhibit prominent catecholase activity in methanol following the oxidation of 3,5-di-tert-butyl catechol (DTBC) to the corresponding quinone. Based on the observed turn over frequency of 1 (25.19 h?1) and 2 (10.76 h?1), the monomeric complex demonstrates more catechol mimetic oxidation than the dimer. A plausible mechanism of catecholase activity has been discussed.