Anticancer potential of copper(i) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands.

In this paper, the isopropyl ester derivatives L and L of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(i) phosphane complexes 1-4. They were synthesized by the reaction of [Cu(CHCN)]PF and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with L and L ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, H-, C- and P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS).

Anticancer activity of new water-soluble sulfonated thiosemicarbazone copper(II) complexes targeting disulfide isomerase.

Copper complexes have shown promising anticancer properties, but they are often poorly soluble in aqueous solutions, thus limiting their possible medical developments and applications. We have recently isolated some copper(II) complexes with salicylaldehyde thiosemicarbazone ligands exhibiting remarkable nanomolar cytotoxic activity, but in vivo tests evidenced several difficulties related to their poor solubility. To overcome these limitations and increase solubility in aqueous solution, herein we report the synthetic strategy that led to the introduction of the sulfonic group on the ligands, then separated as salts (NaHL - NaHL), as well as the synthesis and characterization of the related copper(II) complexes.

Synthesis and Investigations of the Antitumor Effects of First-Row Transition Metal(II) Complexes Supported by Two Fluorinated and Non-Fluorinated β-Diketonates.

The 3 transition metal (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)) complexes, supported by anions of sterically demanding β-diketones, 1,3-dimesitylpropane-1,3-dione (HL) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HL), were synthesized and evaluated for their antitumor activity. To assess the biological effects of substituents on phenyl moieties, we also synthesized and investigated the analogous metal(II) complexes of the anion of the less bulky 1,3-diphenylpropane-1,3-dione (HL) ligand. The compounds [Cu(L)], [Cu(L)] and ([Zn(L)]) were characterized by X-ray crystallography.

Synthesis, characterization and cytotoxicity of gallium(III)-dithiocarbamate complexes.

A library of homoleptic mononuclear Ga(III) complexes of the general formula [Ga(DTC)], where DTC is an alicyclic or a linear dithiocarbamate chelator, is reported. The complexes were prepared in high yields starting from Ga(NO)·6HO and fully characterized by elemental analysis and IR and NMR spectroscopy. Crystals of five of these complexes were obtained.

Development and Characterization of Tc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer.

Previously, we demonstrated that the Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) cell uptake and tumor radiation doses compared to Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a Tc-/Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel Tc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified.

Synthesis and cytotoxicity studies of Cu(I) and Ag(I) complexes based on sterically hindered β-diketonates with different degrees of fluorination.

Design, synthesis, and antitumor properties of Cu(I) and Ag(I) phosphane complexes supported by the anions of sterically hindered β-diketone ligands, 1,3-dimesitylpropane-1,3-dione (HL) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HL) featuring trifluoromethyl or methyl groups on the phenyl moieties have been reported. In order to compare the biological effects of substituents on the phenyl moieties, the analogous copper(I) and silver(I) complexes of the anion of the parent 1,3-diphenylpropane-1,3-dione (HL) ligand were also synthesized and included in the study. In the syntheses of the Cu(I) and Ag(I) complexes, the phosphane coligands triphenylphosphine (PPh) and 1,3,5-triaza-7-phosphaadamantane (PTA) were used to stabilize silver and copper in the +1 oxidation state, preventing the metal ion reduction to Ag(0) or oxidation to Cu(II), respectively.

The prognostic role of gene polymorphisms in patients with indolent non-Hodgkin lymphomas and mantle-cell lymphoma receiving bendamustine and rituximab: results of the 5-year follow-up study.

The variability in disease outcome for indolent non-Hodgkin lymphomas (iNHL) and mantle-cell lymphoma (MCL) could be related to single nucleotide polymorphisms (SNPs) in genes that affect immune and inflammatory response. We investigated SNPs that could have a prognostic role for patients receiving bendamustine and rituximab (BR). All samples were genotyped for the IL-2 (rs2069762), IL-10 (rs1800890, rs10494879), VEGFA (rs3025039), IL-8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays using TaqMan SNP Genotyping Assays.

Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26 leukemia stem cells.

In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation.

Novel Biotinylated Cu(II)-Phenanthroline Complexes: 2D and 3D Cytotoxic Activity and Mechanistic Insight.

The interest in the use of copper as a metal scaffold for the development of novel chemotherapeutics has considerably grown in recent years. This is mainly due to the relatively lower toxicity of copper complexes with respect to platinum drugs (i.e.

Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management.

Bis(pyrazol-1-yl)acetic acid (HC(pz)COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz)COOH) were converted into the methyl ester derivatives (L) and (L), respectively, and were used for the preparation of silver(I) complexes -. The Ag(I) complexes were prepared by the reaction of AgNO and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh) with L and L in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors.

Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis.

A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential in vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake.

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration.

Kiteplatin, [PtCl(-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand -1,2-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, ,,-[PtCl(OBz)(-1,4-DACH)] (; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines.

Glucose-coated superparamagnetic iron oxide nanoparticles prepared by metal vapor synthesis can target GLUT1 overexpressing tumors: In vitro tests and in vivo preliminary assessment.

Superparamagnetic iron oxide nanoparticles (SPIONs) coated with glucose (Glc-SPIONs) were prepared by a new approach called Metal Vapor Synthesis (MVS) and their morphological/structural features were investigated by transmission electron microscopy (TEM) and dynamic light scattering. TEM analysis revealed the presence of small roundish crystalline iron oxide nanoparticles in the organic amorphous phase of glucose, The particles were distributed in a narrow range (1.5 nm-3.

Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects.

Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance.

Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study).

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an "inflammatory status" during nilotinib that may explain the increased incidence of AOEs.

Effect of chirality on the anticancer activity of Pt(II) and Pt(IV) complexes containing 1,2 and 1,2 enantiomers of the -1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin.

Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(II) and four platinum(IV)), all containing unsaturated cyclic diamine -1,2-diamino-4-cyclohexene (DACHEX) as a substitute for the -1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and H-NMR spectroscopy. For the four Pt(IV) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activation .

Pt(iv) complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity.

The Pt(iv) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(ii) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(iv) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(iv) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied.

Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action.

A series of neutral mixed-ligand [HB(pz)]Ag(PR) silver(I) complexes (PR = tertiary phosphine, [HB(pz)] = tris(pyrazolyl)borate anion), and the corresponding homoleptic [Ag(PR)]BF compounds have been synthesized and fully characterized. Silver compounds were screened for their antiproliferative activities against a wide panel of human cancer cells derived from solid tumors and endowed with different platinum drug sensitivity. Mixed-ligand complexes were generally more effective than the corresponding homoleptic derivatives, but the most active compounds were [HB(pz)]Ag(PPh) () and [Ag(PPh)]BF (), both comprising the lipophilic PPh phosphine ligand.

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones.

Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (, -NH; , -NHMe; , -NHEt) have been prepared and characterized. In both the X-ray structures of and , two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in and nitrate in ) or in the co-ligand (water in and methanol in ). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes and confirmed the presence of such different species in the solution.

In vitro and in vivo anticancer activity of tridentate thiosemicarbazone copper complexes: Unravelling an unexplored pharmacological target.

Certain metal complexes can have a great antitumor activity, as the use of cisplatin in therapy has been demonstrating for the past fifty years. Copper complexes, in particular, have attracted much attention as an example of anticancer compounds based on an endogenous metal. In this paper we present the synthesis and the activity of a series of copper(II) complexes with variously substituted salicylaldehyde thiosemicarbazone ligands.

Platinum(IV) Complexes of -1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance.

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine -1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo.

Anticancer activity, DNA binding and cell mechanistic studies of estrogen-functionalised Cu(II) complexes.

Four estrogen-functionalised copper complexes were synthesised and investigated as electrochemical active DNA binding and cleavage agents. These complexes strategically contain a biocompatible metal centre [Cu(II)], a planar aromatic ligand as DNA intercalative agent and an estradiol-derivative moiety which acts as delivery vector to target estrogen-receptor-positive (ER+) cancer cells. Cytotoxic activity was studied over a panel of estrogen-receptor-positive (ER+) and negative (ER-) human cancer cell lines by means of both 2D and 3D cell viability studies.

A minimal structural variation can overcome tumour resistance of oxaliplatin: the case of 4,5-dehydrogenation of the cyclohexane ring.

A new family of anticancer compounds has been derived from oxaliplatin by inserting a double-bond between carbons 4 and 5 of the 1,2-diaminocyclohexane ring. Testing against a panel of human tumour cell lines including cervical (A431), ovarian (2008), and colon carcinomas (HCT-15 and LoVo), and two oxaliplatin-resistant clones (LoVo OXP and LoVo MDR) has shown that the new compounds have, in general, equal if not better cytotoxic activity and are able to overcome the oxaliplatin-resistance. Moreover, the oxalato derivative induced lipid droplets increase in LoVo OXP cells thus suggesting the involvement of metabolism stress in its mechanism of action.