Adoración G. Quiroga

Palladated and platinated complexes derived from phenylacetaldehyde thiosemicarbazone with cytotoxic activity in cis- DDP resistant tumor cells. Formation of DNA interstrand cross-links by these complexes

In the present paper we report the synthesis and characterization by 1H 13C NMR and heteronuclear 2D NMR spectroscopies of two new metallic complexes derived from phenylacetaldehyde thiosemincarbazone: Pt(C9H11N3S)Cl2, compound 2, and Pd(C9H11N3S)Cl2, compound 3. The testing of the cytotoxic activity of these compounds against several human and murine cell lines sensitive and resistant to cis-DDP suggests that compounds 2 and 3 may be considered potential anticancer agents since they exhibit 1C50 values in a microM range similar to cisplatin (cis-DDP). The cytotoxic activity of these compounds is higher in cis-DDP-resistant tumor cells than that of other antitumor drugs such as etoposide and adriamycin. On the other hand, the analysis of the interaction of compounds 2 and 3 with linear plasmid DNA indicate that both compounds, particularly compound 3, have an enhanced capacity to form DNA interstrand cross-links in comparison with cis-DDP.

Synthesis and characterization of Pd(II) and Pt(II) complexes of p-isopropylbenzaldehyde N-protected thiosemicarbazones. Cytotoxic activity against ras-transformed cells.

Cytotoxicity tests in tumor cells sensitive to cis-DDP (HL-60, JURKAT, Hela and 3T3) and in tumor cells transformed by ras oncogenes and resistant to cis-DDP (Pam 212-ras) show that cyclometallated complexes 1a [Pd(p-is.TSCN-NHMe)]4, 2b [Pt(p-is.TSCN-NMe2)]4 and 4a [Pd(p-is.TSCN-NHex)]4 may be endowed with specific cytotoxic properties. In fact, these three novel metal-thiosemicarbazone compounds kill Pam 212-ras cells through apoptosis induction. These results, together with others recently published, indicate that the design and synthesis of metallated-thiosemicarbazone compounds may lead to the discovery of novel antitumor agents able to circumvent cis-DDP resistance, in particular tumor cell lines.

Understanding trans platinum complexes as potential antitumor drugs beyond targeting DNA.

This focused review is devoted to our advances in developing trans platinum complexes as antitumoral complexes, in particular those bearing aliphatic amines. It includes some fundamental aspects of the understanding of non conventional metallodrug mechanism. The perspective is arranged by those fundamental aspects and within each section only the most successful examples have been included and also those in which clearly SARs (structure activity relationships) have been observed.

Binuclear chloro-bridged palladated and platinated complexes derived from p-isopropylbenzaldehyde thiosemicarbazone with cytotoxicity against cisplatin resistant tumor cell lines

Two novel dimeric chloro-bridged complexes [Pd (p-is. TSCN) (mu-Cl)]2, 2, and [Pt (p-is. TSCN)(mu-Cl)]2, 3, where p-is. TSCN = p-isopropylbenzaldehyde thiosemicarbazone, 1, have been synthesized and characterized by IR and NMR spectroscopy. The in vitro antitumor activity shown by both compounds against several human and murine cell lines sensitive and resistant to the clinically-used drug cisplatin (cis-DDP) suggests that compounds 2 and 3 may be endowed with important anticancer properties. Thus, compounds 2 and 3 not only show IC50 values in the microM range as cis-DDP but also display cytotoxic activity in tumor cell lines resistant to this drug. The analysis of the interaction of these binuclear p-is. TSCN compounds with DNA secondary and tertiary structures indicate that they form DNA interhelical cross-links, a biochemical property that may be involved in their mechanism of action.

Peculiar features in the crystal structure of the adduct formed between cis-PtI2(NH3)2 and hen egg white lysozyme.

The reactivity of cis-diamminediiodidoplatinum(II), cis-PtI2(NH3)2, the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 Å resolution. In this adduct, the Pt(II) center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt(II) binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL-cisplatin, previously described; differences are stressed and their important mechanistic implications discussed.

Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(II) anticancer complexes

Three (15)N-labelled trans-Pt(ii) amine complexes with isopropylamine ((15)N-ipa), methylamine ((15)N-ma) and dimethylamine ((15)N-dma) have been prepared and characterized. 2D [(1)H,(15)N] HSQC NMR spectroscopy was used to obtain the rate and equilibrium constants for the aquation of trans-[PtCl(2)((15)N-ipa)((15)N-ma)] ((15)N-1), trans-[PtCl(2)((15)N-dma)((15)N-ma)] ((15)N-2) and trans-[PtCl(2)((15)N-dma)((15)N-ipa)] ((15)N-) in 100 mM NaClO(4) solutions at 298 K. New (15)N shift ranges for H(2)N-Pt(II)-N and HN-Pt(II)-N groups are reported. Formation of the diaqua complex was not observed for and accounted for <2% of the species at equilibrium for 1 and 2 . The first aquation step is significantly faster for 2 (k(1) = 14 x 10(-5) s(-1)) than for the two complexes with the bulkier ipa ligand (k(1) = 5.5 x 10(-5) s(-1) (), 6.1 x 10(-5) s(-1) (3)), but 2 is the least aquated of the three complexes at equilibrium. The pK(a) values for the monoaqua adducts of 1-3 are similar (5.98, 5.85 and 5.91, respectively) and 0.4 pH units lower than the related cis complex cis-[PtCl(2)(dma)(2)], indicating a smaller proportion of more reactive aqua species will exist at physiological pH. The pK(a) values for the diaqua adduct of 2 (4.59 and 7.98) are 0.3-0.6 pH units higher than those of 1(4.31 and 7.30) and 3 (4.28 and 7.29), which have very similar values. The speciation profiles of 1-3 , calculated on the basis of the calculated equilibrium and dissociation constants, indicate that <1% hydrolyzed species will exist under physiological conditions in cancer cells. The cytotoxicity of 1-3 (non-(15)N-labelled) was assessed in three cancer lines (SF268, MCF-7 and NCI-H460). The new trans-Pt(ii) diamine complex 2 is more active than 1 and 3 in all cases and is more potent than cisplatin in the MCF-7 adenocarcinoma cell line.

Novel clioquinol and its analogous platinum complexes: importance, role of the halogen substitution and the hydroxyl group of the ligand.

In this communication, we present the synthesis of new platinum complexes based on hydroxyquinoline ligands. We demonstrate the importance and the role of the halogen substitution as well as the chelation, which are essential structural characteristics for finding good cytotoxicities.

Proteins as Possible Targets for Cytotoxic trans-Platinum(II) Complexes with Aliphatic Amine Ligands: Further Exceptions to the DNA Paradigm

The reactivity of three cytotoxic trans‐PtII complexes bearing aliphatic amine ligands, with transferrin and single‐stranded oligonucleotides as DNA models, was investigated by ESI‐MS and the results obtained are discussed in comparison with cisplatin. Tandem MS studies provided additional information on the preferential Pt binding sites. To determine whether trans‐PtII complexes can migrate from a peptide to an oligonucleotide, transfer experiments were also performed using ESI‐MS, and competitive binding of the trans‐PtII complexes toward a model peptide and different oligonucleotides was also investigated. Significant differences in the reactivity of the trans complexes with respect to cisplatin were observed. In general, adduct formation with the selected peptide is favored for the trans compounds, whereas cisplatin shows a preference for oligonucleotides, especially if adjacent G–G residues are present. The results are discussed in relation to the possible mechanism of action of the trans‐PtII complexes.

Cytotoxic Profile and Peculiar Reactivity with Biomolecules of a Novel "Rule-Breaker" Iodidoplatinum(II) Complex.

Novel and surprising biological properties were disclosed for the platinum(II) complex cis-diiodidodiisopropylamineplatinum(II). Remarkably, this new platinum(II) complex manifests pronounced antiproliferative properties in vitro, in some cases superior to those of cisplatin. A peculiar reactivity with the model protein cytochrome c was indeed highlighted based on the loss of amine ligands and retention of iodides.

A cycloplatinated compound of p-isopropylbenzaldehyde thiosemicarbazone and its chloro-bridged derivative induce apoptosis in cis-DDP resistant cells which overexpress the H-ras oncogene.

cis-Diamminedichloroplatinum(II) (cis-DDP) is a widely used antitumour drug which produces important damage on the DNA inducing apoptosis in several cell lines. We have analyzed the cytotoxic activity of novel cyclometallated complexes of p-isopropylbenzaldehyde thiosemicarbazone (p-is.TSCN) and their dimeric chloro-bridged derivatives in murine keratinocytes transformed by the H-ras oncogene which are resistant to cis-DDP (Pam-ras cells). The data show that, in contrast with cis-DDP, the tetrameric cycloplatinated complex [Pt(p-is.TSCN)]4 and its dimeric chloro-bridged derivative [Pt(microCl)(p-is.TSCN)]2 have a good in vitro therapeutic index when comparing the cytotoxicity in Pam-ras cells to normal murine keratinocytes (Pam 212 cells) since they induce cell death in Pam-ras cells at drug concentrations significantly lower than those needed to kill Pam 212 cells. At equitoxic doses (IC90), both complexes produce characteristic features of apoptosis in Pam-ras cells together with a drastic decrease in levels of H-ras protein. These effects are not observed when the cells are treated with the IC90 of the cis-DDP drug nor the p-is.TSCN ligand. Altogether, these results suggest that the platinum compounds [Pt(p-is.TSCN)]4 and [Pt(microCl)(p-is.TSCN)]2 might have potential as antitumour agents in view of their specific induction of apoptosis in cis-DDP resistant cells.