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.

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.

Novel tetranuclear orthometalated complexes of Pd(II) and Pt(II) derived from p-isopropylbenzaldehyde thiosemicarbazone with cytotoxic activity in cis-DDP resistant tumor cell lines. Interaction of these complexes with DNA.

The reaction of p-isopropylbenzaldehyde thiosemicarbazone [p-is.TSCN], 1, with palladium(II) acetate and potassium tetrachloroplatinate yielded two tetrameric orthopalladated isomers, [Pd(p-is.TSCN)]4 (complexes 2 and 3), and the platinum analogue [Pt(p-is.TSCN)]4 (complex 4), respectively. All of these complexes contain the thiosemicarbazone bonded as a terdentate ligand to the metallic atom, through the thiol sulfur, the azomethinic nitrogen and the ortho carbon of the p-isopropylphenyl ring to which the imine group is attached to as deduced from the study of the IR, NMR, and XRD spectra of complexes 2 and 4. Complexes 2 and 4 crystallize in the centrosymmetric monoclinic space group C2/c, with Z = 8. Unit cell parameters for complex 2 are as follows: a = 25.742(5) A, b = 19.560(4) A, c = 24.199(5) A, beta = 101.70(3)o. Unit cell parameters for complex 4 are as follows: a = 25.8728(19) A, b = 19. 5053(14) A, c = 24.0899(16) A, beta = 101.305(2)o. As can be deduced from the NMR study, the palladated isomers 2 and 3 interconvert in DMSO which may be a consequence of the existence in both complexes of a flexible eight-membered ring with alternating Pd-S atoms. The testing of the cytotoxic activity of these compounds against several human and murine cell lines sensitive and resistant to cisplatin (cis-DDP) suggests that compounds 2, 3, and 4 may be endowed with important anticancer properties since they elicit IC50 values in the microM range as does the clinically used drug cis-DDP, and, moreover, they display cytotoxic activity in tumor lines resistant to cis-DDP. The analysis of the interaction of these novel tetrameric cyclometalated compounds with DNA suggests that they form DNA interhelical cross-links.

Cytotoxicity, DNA binding, and reactivity against nucleosides of platinum (II) and (IV) spermine compounds.

We describe the synthesis and characterization of a [sperH4][PtCl4]2 salt and of five binuclear platinum (II) and (IV)-spermine compounds of formula [(PtCl2)2(sper)], cis-[(Pt(CH2(COO)2)2(sper)], cis-[(PtCBDCA)2(sper)], (CBDCA = 1,1'-cyclobutanedicarboxylate), cis-trans-cis[(PtCl2(OH)2)2(sper)], and cis-[(PtCl4)2(sper)], respectively. The 1H and 195Pt-NMR analysis of the complexes formed between these compounds and nucleosides indicated that the Pt centers show preferential binding to the N(7) of guanosine and adenosine residues, also being capable of forming bridged structures through the N(7) and N(1). The synthesized Pt-spermine compounds do not form complexes with cytidine residues at 37 degrees C. The circular dichroism, melting, and electrophoretic data of the compounds-DNA complexes show that the Pt(IV)-spermine complexes induce lower DNA conformational changes than their Pt(II) analogs. These results correlate with the IC50 values obtained against MDA-MB 468 and HL-60 human cancer cells which are higher than those of cis-DDP. The [sperH4][PtCl4]2 salt produces a high level of DNA modification and exhibits IC50 values lower than those of cis-DDP.

Synthesis, characterization, and DNA modification induced by a novel Pt-berenil compound with cytotoxic activity.

In the present paper, we show that the reaction of the antipyranosomatid berenil drug with K2PtCl4 resulted in the synthesis of a covalent (Pt(II)-berenil compound of formula [Pt2Cl4(berenil)2]Cl4.4H2O as shown by IR, 1H, 13C, and 195Pt-NMR. The Pt-berenil compound was tested for in vitro antitumor activity against HL-60 and U-937 human leukemic cells. The results show that the LC70 values of the Pt-berenil are about two-fold lower than those of cis-DDP in both HL-60 and U-937 cell lines. Melting data of Pt-berenil:DNA and berenil:DNA complexes indicate that the platinated compound produces on a DNA secondary structure higher compaction than the berenil ligand. The mobility in agarose gels and the circular dichroism spectra of the compounds:DNA complexes revealed, moreover, that both induce drastic changes on a DNA secondary and tertiary structure. The total reflection X-ray fluorescence data showed, in additIon that DNA platination in Pt-berenil:DNA complexes occurs within minutes after addition of the drug, in contrast to what that observed in cis-DDP:DNA complexes. On the basis of these results, we propose that in Pt-berenil, the berenil ligand acts as a carrier of the active cis-P(II) centers towards DNA.

Synthesis, crystal structure, and biological activity of a Pt-dipyridamole salt.

In the present paper we present data on the synthesis, crystal structure and biological activity of bis(dipyridamole) tetrachloroplatinate(II).dipyridamole.dihydrate, [dpmH]2 PtCl4.dpm.2H2O. The crystals are Triclinic P1 with a = 11.490(2) A, b = 13.630(2) A, c = 15.81(1) A, a = 100.97(2) degrees, beta = 100.89(3) degrees, gamma = 112.35(1) degrees, Z = 1, M = 1885.9, Dx = 1.46 g/cm3, MoK alpha (lambda = 0.71069 A), mu = 0.0184 mm-1, R = 4.4%, Rw = 5.0%, 3231 (1 > 2 sigma (I)). The structure is stabilized by a hydrogen-bonding network. It was observed that although dpm alone is not able to alter the electrophoretic mobility of pUC8 DNA forms, the synthesized Pt-dpm compound substantially modifies the DNA conformation since it significantly alters the electrophoretic mobility of nicked and closed circular forms of pUC8 DNA. However, the alteration in mobility of pUC8 DNA induced by this compound upon binding is lower than that induced by cis-DDP. The analysis of the antiproliferative activity of the Pt-dpm salt against MDA-MB 468 (breast carcinoma) and HL-60 (leukemia) human cancer cells showed that this compound has ID50 values of 0.87 microM and 0.65 microM, respectively. Interestingly, it was found out that although the dpm molecule does not present any significant antiproliferative activity, the ID50 values of Pt-dpm are about 3-fold and 7-fold lower than those of cis-DDP and K2PtCl4, respectively. Altogether the biological data suggest that in Pt-dpm a synergic effect between cation and anion is produced.

Platinum (II) and (IV) spermidine complexes. Synthesis, characterization, and biological studies.

By reaction of K2PtCl4 with spermidine we have synthesized two tris-platinum covalent compounds of formula (PtI2)3(sper)2 and (PtCl2)3(sper)2, one ionic compound of formula (sperH3)2(PtCl4)3, and another one of a covalent nature of formula (PtCl2sperH)2 (PtCl4) having a partially protonated spermidine residue. Treatment of the tris-platinum compounds with hydrogen peroxide and hydrochloric acid led to the production of two compounds of formula cis-trans-cis-(PtIVCl2(OH)2)3(sper)2 and cis-(PtIVCl4)3(sper)2, respectively. All of them have been characterized by IR and 1H MNR spectroscopy and tested for their ability to interact with pUC8 plasmid DNA by the use of UV, CD, and electrophoretic techniques. The results suggest that all of these compounds modify the secondary structure of the double helix. We observed that the alteration in electrophoretic mobility of nicked and closed circular forms of DNA induced by the Pt(II) complexes is higher than that induced by the Pt(IV) complexes. The synthesized compounds were also assayed for antitumor activity in vitro against breast (MDA-MB468) and leukemia (HL-60) tumor cells. Only three of these complexes may be regarded as potential antitumor agents, since their ID50 values are lower than 10 micrograms/ml.

Analysis of two cycloplatinated compounds derived from N-(4-methoxyphenyl)-alpha-benzoylbenzylidenamine. Comparison of the activity of these compounds with other isostructural cyclopalladated compounds.

In the present paper we report the synthesis, structural characterization, biochemical properties, and antiproliferative activity of two organo-cis-platinum cyclometalated compounds of formula [M(4-OMeC6H4N=C(COC6H5)C6H4)X]2, where M = Pt and X=Cl (4) or OAc (5). The IR and 1H and 13C NMR data of the chloro-bridged compound 4 showed that it has a planar structure. As indicated by IR and 1H and 13C NMR, the acetate-bridged compound 5 has an open-book shape structure. This structure was further confirmed by X-ray diffraction. The comparison of the biochemical properties and antiproliferative activity of these compounds relative to the isostructural palladium compounds [Pd(4-OMeC6H4N=C(COC6H5)C6H4)X]2 [X = AcO (1) and (2) or Cl (3)] indicated that the activity of compounds 4 and 5 is higher than that of the corresponding isostructural compounds 3 and 1-2, respectively, since their ID50 are 2-9-fold lower. It seems that there are not differences in the antiproliferative activity of all these compounds against leukemia HL-60 cells or mammary cancer MDA-MB 468 cells. Compounds 4 and 5 modify also the DNA structure of the oc and ccc forms of plasmid DNA. The acetate-bridged compound 5 showed the highest antiproliferative activity which is even higher than that of cis-DPP. Our data indicate that the Pt(II) compounds are more active than those having Pd(II) as the metal center.

Palladium (II) compounds of putrescine and spermine. Synthesis, characterization, and DNA-binding and antitumor properties.

The reaction of putrescine (Put) with K2PdCl4 and PdCl2 resulted in the synthesis of compounds of formula [PutH2][PdCl4] and [Pd2Cl4(Put)2]. Compounds of formula [PdCl2(SpermH2)][PdCl4] and [Pd2Cl4(Sperm)] have been also synthesized by reaction of spermine (Sperm) with K2PdCl4. The structure of all these compounds has been analyzed by IR and 1H NMR. UV and CD spectroscopic data have shown that all the Pd(II)-polyamine compounds synthesized induce conformational changes in the circular forms of plasmid DNA. Determinations by electrophoresis in agarose gels of the mobility of the DNA in drug:DNA complexes indicated that only the Pd(II)-putrescine compounds have the ability to induce significant conformational changes in the covalently closed circular (ccc) form of the pUC8 plasmid DNA. The Pd(II)-putrescine and Pd(II)-spermine compounds were also assayed for in vitro antiproliferative activity against MDA-MB 468 and HL-60 human cancer cells. The results suggest that the putrescine complexes may be regarded as potential antitumor agents because the ID50 value of all of the Pd(II)-putrescine complexes is twofold lower than the ID50 of cis-DDP. Our data also show that, on the other hand, the Pd(II)-spermine compounds have low antiproliferative activity.

Platinum complexes of p- and m-aminobenzamidine. Synthesis, characterization, and cytotoxic activity.

Four platinum(II) aminobenzamidine complexes have been prepared and characterized by IR and 1H and 13C NMR spectroscopy, and tested for their ability to interact with the nicked and closed circular forms of the pUC8 plasmid DNA. The results show that the complexes of formula [Pt(LH)2Cl2]2X have a cis- geometry with an amino-Pt bonding, where L is either p- or m-aminobenzamidine and where 2X is 2Cl- or PtCl4(2-). It was observed that these complexes significantly alter the electrophoretic mobility of nicked and closed circular forms of DNA and that the alteration in electrophoretic mobility due to Pt(II)-p-aminobenzamidine binding is higher than that due to Pt(II)-m-aminobenzamidine. No difference in mobility was observed whether the DNA interacted with complexes having as counteranion Cl- or PtCl4(2-). The synthesized compounds were, in addition, assayed for antitumor activity in vitro against colon (CX-1), lung (LX-1), and mammary (MX-1) human tumor cells. The results show that these complexes inhibited the multiplication of the tumor cells and that they show higher specificity for lung cells.

Palladium(II) salt and complexes of spermidine with a six-member chelate ring. Synthesis, characterization, and initial DNA-binding and antitumor studies.

By reaction of spermidine trihydrochloride with K2PdCl4 and PdCl2 at different pH's, we have synthesized the [sperH3]2[PdCl4]3 (I), [PdCl2(sperH)]2[PdCl4] (II), and [(PdCl2)3(sper)2] (III) compounds. The structure of these compounds was studied by IR and 1H NMR; complex II was analyzed by x-ray diffraction. In this complex the spermidine is attached to the PdCl2 group forming a six-member chelate ring with a protonated terminal amine group. The crystal of [PdCl2(sperH)]2[PdCl4] x 2H2O (II) is monoclinic, P2(1)/n, with a = 7.023(1) A, b = 12.662(1) A, c = 18.435(3) A, and beta = 99.95(1) degrees, Z = 4, R = 0.051, and Rw = 0.058 on the basis of 2690 independent reflections. We have compared the antitumor activity in vitro against the isolated human breast carcinoma MDA-MB 468 cell line of compounds I, II, and III with that of cis-diamminedichloroplatinum(II), cis-DDP. The results show that compounds III and III have values of ID50 similar (0.74 microgram/ml) or even lower (0.56 microgram/ml) than cis-DDP (0.80 microgram/ml). We also observed that compounds I, II, and III have the ability to induce conformational changes in covalently closed circular (ccc) form of the pUC8 plasmid DNA. Compounds II and III also induce conformational changes in the open circular (oc) form of this plasmid.