Mononuclear Pd(II) and Pt(II) complexes with an α-N-heterocyclic thiosemicarbazone: Cytotoxicity, solution behaviour and interaction: Versus proven models from biological media

Two Pd(ii) and Pt(ii) complexes with two pyrrol-2-carbaldehyde N-p-chlorophenylthiosemicarbazone ligands are designed and characterized showing mononuclear structures. An important pharmacological property for both compounds is the high selectivity for tumor cells and a lack of activity in healthy cells. The Pd(ii) compound shows a higher antitumor activity and selectivity than the Pt(ii) compound. Both complexes present a variety of biological interactions: with DNA models (pBR322 and CT DNA), proteins (lysozyme and RNase) and other biological targets like proteosome. Our results show that the Pd(ii) complex is a more interesting candidate for potential anticancer therapies than the Pt(ii) complex, and we provide new insight into the design and synthesis of palladium compounds as potential antitumor agents.This work was supported by the following grants for the Spanish MINECO: SAF-2012-34424, CTQ2015-68779R and CTQ2015-70371-RED

A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

<p>Abstract</p> <p>Background</p> <p>Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd₂[<it>S_(-)</it>C², N-dmpa]₂(μ-dppe)Cl₂} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.</p> <p>Methods</p> <p>B16F10-Nex2 cells were treated <it>in vitro </it>with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated <it>in vitro </it>with C7a.</p> <p>Results</p> <p>Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages <it>in vitro</it>, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.</p> <p>Conclusions</p> <p>The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.</p

Cytotoxic effects of metal complexes of biogenic polyamines. I. Platinum(II) spermidine compounds: prediction of their antitumour activity

Cytotoxicity and cell growth inhibition studies were performed for three distinct polynuclear platinum(II) complexes of spermidine, which showed to have significant cytotoxic and antiproliferative properties on the HeLa cancer cell line. The chemical environment of the metal centres in the drugs, as well as the coordination pattern of the ligand, were found to be strongly determinant of their cytotoxic ability. In the light of the results gathered, the most effective anticancer compound among the ones tested (IC50=5 [mu]M) was found to be the one displaying three difunctional (PtCl2N2) moieties ((PtCl2)3(spd)2). Both the cytotoxic activity and the antiproliferative properties of the complexes studied showed to be irreversible for all the concentrations tested.http://www.sciencedirect.com/science/article/B6T20-44P6YK2-3/1/19b22fc5d0627f0d3a6bc4000beb2fd

Antitumor and cellular pharmacological properties of a novel platinum(IV) complex: trans-[PtCl2(OH)(2)(dimethylamine)(isopropylamine)]

The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl2(OH)(2)(dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl2(dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41 McisR and CH1 cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1 cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1 cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand cross-links in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2. Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins

Determination of catalase activity in samples treated with [ZnCl2(isopropylamine)(2)]: a novel zinc complex that slows down the decay in activity of catalase extracts

Reaction of ZnCl2 with an excess of isopropylamine ligand in water gives [ZnCl2(isopropylamine)2]. This novel zinc complex has been characterized by elemental analysis and 1H-NMR. Interestingly, we have found that [ZnCl2(isopropylamine)2] markedly retards the decay in activity of catalase extracts. In fact, catalase extracts (0.075 mg of protein ml−1) may retain more than 80% of their initial enzymatic activity within the first 10 hours of incubation with 0.10 μM [ZnCl2(isopropylamine)2] while the activity of control extracts decreases to less than 50% of the initial value. Moreover, after 24 hours of treatment with [ZnCl2(isopropylamine)2] under the above-mentioned conditions, 70% of the initial enzymatic activity is still retained by catalase extracts while the activity of control untreated extracts drops to 17% of the initial value. On the other hand, our results show that after incubation of catalase extracts with [ZnCl2(isopropylamine)2] the supernatants obtained by centrifugation of the extracts contain a higher amount of active catalase than the supernatants of control untreated catalase extracts. Moreover, [ZnCl2(isopropylamine)2] induces precipitation of a large amount of contaminant proteins present in the catalase extracts. Altogether, these data indicate that treatment of catalase extracts with [ZnCl2(isopropylamine)2] both increases the pureness of catalase solutions and slows down the decay in catalase activity. We believe that [ZnCl2(isopropylamine)2] may be useful as a stabilizing agent for enzyme activity assays with crude catalase extracts

An androgenic steroid delivery vector that imparts activity to a non-conventional platinum(II) metallo-drug

A range of androgen conjugates with non-conventional platinum(II) complexes have been synthesised with the aim of targeting tumour cells since many display elevated levels of the androgen receptor. The androgenic platinum conjugates are delivered into selected cells with improved efficiency (when compared to their non-steroidal analogues). The act of conjugating an androgen to a platinum(II) complex resulted in synergistic effects between the metallic centre and the steroidal ligand, creating highly potent platinum(II) complexes from the inactive components