Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates

Belicchi-Ferrari, Marisa; Bisceglie, Franco; Buschini, Annamaria; Franzoni, Susanna; Pelosi, Giorgio; Pinelli, Silvana; Tarasconi, Pieralberto; Tavone, Matteo

doi:10.1016/j.jinorgbio.2009.11.002

Cited by 40 publications

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References 40 publications

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“…This new copper complex showed a strong cytotoxic activity [13]. Citronellal thiosemicarbazone is a mildly active agent (IC 50 = 40 μM) and inhibits proliferation by inducing apoptosis [12], but the ethylmorpholine thiosemicarbazone does not even slightly inhibit proliferation [13]. The respective copper complexes result to have an IC 50 of 14.8 μM [Cu(S-tcitr) 2 ] (with no apoptosis) and 2.3 μM [Cu(Etmorph-S-tcitr) 2 ] (with apoptosis).…”

Section: Introductionmentioning

confidence: 94%

“…To compare the toxic effects of these two copper(II) complexes, differing only for the ethylmorpholino group, we used human histiocytic lymphoma line U937 as a model. This new copper complex showed a strong cytotoxic activity [13]. Citronellal thiosemicarbazone is a mildly active agent (IC 50 = 40 μM) and inhibits proliferation by inducing apoptosis [12], but the ethylmorpholine thiosemicarbazone does not even slightly inhibit proliferation [13].…”

Section: Introductionmentioning

confidence: 99%

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Copper(II) thiosemicarbazonate molecular modifications modulate apoptotic and oxidative effects on U937 cell line

Bisceglie

Pinelli

Alinovi

et al. 2012

Journal of Inorganic Biochemistry

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Copper(II) thiosemicarbazonate molecular modifications modulate apoptotic and oxidative effects on U937 cell line

Bisceglie

Pinelli

Alinovi

et al. 2012

Journal of Inorganic Biochemistry

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“…In addition, the TSC complexes with transition metals, such as copper and nickel, have also been shown to display interesting pharmacological properties 2,21 , including antiretroviral activity, growth inhibition of different bacteria and moulds and a tumour cell line-specific antiproliferative activity [22][23][24][25][26][27][28][29] . A multi-target mode of action also seems to apply to TSC-metal complexes, which appear to be more potent and selective antineoplastic agents than their uncomplexed counterparts.…”

mentioning

confidence: 99%

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Baruffini

Ruotolo

Bisceglie

et al. 2020

Sci Rep

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thiosemicarbazones (tSc) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Ribonucleotide reductase (RNR) is considered one of the main targets of TSCs, yet, the existence of additional targets, differently responsible for the multifaceted activities of TSCs and their metal complexes has been proposed. to set the basis for a more comprehensive delineation of their mode of action, we chemogenomically profiled the cellular effects of bis(citronellalthiosemicar bazonato)nickel(ii) [ni(S-tcitr) 2 ] using the unicellular eukaryote Saccharomyces cerevisiae as a model organism. Two complementary genomic phenotyping screens led to the identification of 269 sensitive and 56 tolerant deletion mutant strains and of 14 genes that when overexpressed make yeast cells resistant to an otherwise lethal concentration of Ni(S-tcitr) 2. Chromatin remodeling, cytoskeleton organization, mitochondrial function and iron metabolism were identified as lead cellular processes responsible for ni(S-tcitr) 2 toxicity. The latter process, and particularly glutaredoxin-mediated iron loading of RNR, was found to be affected by Ni(S-tcitr) 2. Given the multiple pathways regulated by glutaredoxins, targeting of these proteins by Ni(S-tcitr) 2 can negatively affect various core cellular processes that may critically contribute to Ni(S-tcitr) 2 cytotoxicity. Originally discovered as antivirals active against smallpox and other viruses 1 , thiosemicarbazones (TSC) are still attracting significant interest as anticancer agents 2-4. The antiproliferative activity of TSCs has been initially ascribed to their metal (e.g., Fe 2+) sequestration capacity and to the inactivation of ribonucleotide reductase (RNR), the enzyme that converts ribonucleotides into deoxyribonucleotides and whose activity correlates with cell proliferation 5,6. However, additional targets have emerged from more recent studies, including topoisomerase II, the metalloenzymes xanthine oxidase and tyrosinase, and the mitochondria signalling pathway 7-11. One of the first TSC tested in phase I clinical trials was 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP) 12. However, these trials revealed severe side effects (mainly gastrointestinal toxicity) and fast inactivation via metabolic conversion (glucuronidation) of 5-HP 4. Further investigation has led to the development of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) 13 , whose efficacy is currently undergoing phase II clinical testing 14-17. This compound shows promising activity against hematologic disorders but not solid tumours 4. The reasons may be an inappropriate drug delivery due to a short plasma half-life, Triapine metabolic conversion, and/or rapid development of drug resistance 4. Recently, phase I clinical trials are being performed to test Triapine in combination therapy with other anticancer drugs 18. Since 2015 4,19,20 , phase I clinical trials were also starte...

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“…Data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2014); data reduction: SAINT; program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg & Putz, 2012) and ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and WinGX (Farrugia, 2012 which are the causative agents of malarya and Chagas′ disease, respectively (Greenbaum et al, 2004;Finch et al, 1999;Wilson et al, 1974;Du et al, 2002). In addition, in the last few years there has been a growing attention towards thiosemicarbazones related to their range of biological properties, as antituberculosis activity (Desai et al, 1984;, antitumor (Vrdoljak et al, 2010), antiproliferative (Belicchi-Ferrari et al, 2010), and anticancer agents (Marzano et al, 2009). Such facts inspired us to synthesis and study the crystal structure determination of the title compound.…”

Section: Related Literaturementioning

confidence: 99%

Crystal structure of [(E)-({2-[3-(2-{(1E)-[(carbamothioylamino)imino]methyl}phenoxy)propoxy]phenyl}methylidene)amino]thiourea with an unknown solvate

et al. 2015

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The title molecule, C19H22N6O2S2, has crystallographically imposed C 2 symmetry, with the central C atom lying on the rotation axis. The O—C—C—C torsion angle for the central chain is −59.22 (16)° and the dihedral angle between the planes of the benzene rings is 75.20 (7)°. In the crystal, N—H⋯O and N—H⋯S interactions link the molecules, forming a three-dimensional network encompassing channels running parallel to the c axis, which account for about 20% of the unit-cell volume. The contribution to the scattering from the highly disordered solvent molecules in these channels was removed with the SQUEEZE routine [Spek (2015). Acta Cryst. C71, 9–18] in PLATON. The stated crystal data for M r, μ etc. do not take these into account.

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Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates

Cited by 40 publications

References 40 publications

Copper(II) thiosemicarbazonate molecular modifications modulate apoptotic and oxidative effects on U937 cell line

Copper(II) thiosemicarbazonate molecular modifications modulate apoptotic and oxidative effects on U937 cell line

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Crystal structure of [(E)-({2-[3-(2-{(1E)-[(carbamothioylamino)imino]methyl}phenoxy)propoxy]phenyl}methylidene)amino]thiourea with an unknown solvate

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