Search

Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF 3 ) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF 3 . Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF 3 , although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF 3 might be the prototype of a family of potential anticancer agents.

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A large number of cancers are treated with cisplatin (CDDP). However, its use is limited by drug resistance, which is often related to intracellular levels of thiol-containing molecules such as glutathione (GSH). The role of GSH in cisplatin-resistant cancer cells is still unclear. GSH may form adducts with CDDP which results in the deactivation of the drug, and, actually, a high intracellular level of GSH was observed in some cisplatin-resistant cancers. To overcome drug resistance, CDDP is often administered in combination with one or more drugs to exploit a possible synergistic effect. In previous studies, we observed that the sensitivity to CDDP of leukemic and ovarian cisplatin-resistant cancer cells was restored in the presence of [Cu(phen) 2 (H 2 O)](ClO 4 ) 2 (C0) (phen is 1,10-phenathroline). In order to clarify the possible interactions between GSH and CDDP, the reactivity and competitive reactions among CDDP, C0 and GSH in binary and ternary mixtures were studied. The investigation was extended also to [Cu(phen)(H 2 O) 2 (ClO 4 ) 2 ] (C10) and GSSG, the oxidized form of GSH. It was observed that CDDP was able to react with the studied copper complexes and with GSH or GSSG. However, in mixtures containing CDDP, GSH or GSSG and C0 or C10, only copper-glutathione complexes were detected, while no platinum-glutathione adducts were found., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The speciation of the potential antitumor agent vanadocene dichloride ([Cp2VCl2], abbreviated with VDC) in the blood plasma was studied by instrumental (EPR, ESI-MS, MS-MS, and electronic absorption spectroscopy) and computational (DFT) methods. The behavior of VDC at pH 7.4 in aqueous solution, the interaction with the most important bioligands of the plasma (oxalate, carbonate, phosphate, lactate, citrate, histidine, and glycine among those with low molecular mass and transferrin and albumin between the proteins) was evaluated. The results suggest that [Cp2VCl2] transforms at physiological pH to [Cp2V(OH)2] and that only oxalate, carbonate, phosphate, and lactate are able to displace the two OH(-) ions to yield [Cp2V(ox)], [Cp2V(CO3)], [Cp2V(lactH(-1))], and [Cp2V(HPO4)]. The formation of the adducts with oxalate, carbonate, lactate, and hydrogen phosphate was confirmed also by ESI-MS and MS-MS spectra. The stability order is [Cp2V(ox)] ≫ [Cp2V(CO3)] > [Cp2V(lactH(-1))] > [Cp2V(HPO4)]. No interaction between VDC and plasma proteins was detected under our experimental conditions. Several model systems containing the bioligands (bL) in the same relative ratio as in the blood samples were also examined. Finally, the speciation of VDC in the plasma was studied. The results obtained show that the model systems behave as the blood plasma and indicate that when V concentration is low (10 μM) VDC is transported in the bloodstream as [Cp2V(ox)]; when V concentration is high (100 μM) oxalate binds only 9.2 μM of [Cp2V](2+), whereas the remaining part distributes between [Cp2V(CO3)] (main species) and [Cp2V(lactH(-1))] (minor species); and when V concentration is in the range 10-100 μM [Cp2V](2+) distributes between [Cp2V(ox)] and [Cp2V(CO3)].

The cytotoxic properties of copper(II) complexes with 1,10-phenanthroline (phen) can be modified by substitution in the phen backbone. For this purpose, Cu(II) complexes with phen, 1,10-phenanthrolin-5,6-dione (phendione) and 1,10-phenanthrolin-5,6-diol (phendiol) have been synthesised and characterised. The crystal structure of [Cu(phendione)2(OH2)(OClO3)](ClO4) is discussed. The complex formation equilibria between Cu(II) and phen or phendione were studied by potentiometric measurements at 25 and 37°C in 0.1 M ionic strength (NaCl). The antitumour activity of the compounds has been tested in vitro against a panel of tumour (DU-145, HEP-G2, SK-MES-1, CCRF-CEM, CCRF-SB) and normal (CRL-7065) human cell lines. The studied compounds generally present an antiproliferative effect greater than that of cisplatin. The phen and phendione ligands present a similar antiproliferative effect against all the tested cells. Phendiol presents an antiproliferative effect 1.3 to 18 times greater than that of phen or phendione for leukemic, lung, prostatic and fibroblast cells, while it presents less activity towards hepatic cells. Complexes with two ligands are more cytotoxic towards all the tested cell lines than complexes with one ligand and are generally more cytotoxic than the ligand alone. Complexes [Cu(phendiol)2(OH2)](ClO4)2 and [Cu(phendione)2(OH2)(OClO3)](ClO4) appear to be the most active compounds for the treatment of SK-MES-1 and HEP-G2 cells, respectively, being at least 18 times more cytotoxic than cisplatin. The studied Cu(II) complexes are characterised by a strong DNA affinity and were found to interact with DNA mainly by groove binding or electrostatic interactions. The complexes appear to act on cells with a mechanism different from that of cisplatin., (Copyright © 2014 Elsevier Inc. All rights reserved.)