ABSTRACT
BACKGROUND: Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. METHODS: We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. RESULTS: In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. CONCLUSION: In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism.
Subject(s)
Antineoplastic Agents/pharmacology , DNA/biosynthesis , Organometallic Compounds/pharmacology , Organoplatinum Compounds/pharmacology , Transcription, Genetic/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis , Cell Cycle , Cell Line, Tumor , Cellular Senescence , Dose-Response Relationship, Drug , Humans , Ligands , Necrosis , Organometallic Compounds/chemical synthesis , Organometallic Compounds/toxicity , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/toxicity , RNA, Messenger/metabolismABSTRACT
BACKGROUND: Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. METHODS: We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. RESULTS: In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. CONCLUSION: In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism (AU)
Subject(s)
Humans , Male , Female , Antineoplastic Agents/pharmacology , DNA/biosynthesis , Antineoplastic Agents/chemical synthesis , Organometallic Compounds/pharmacology , Transcription, Genetic , Antineoplastic Agents/toxicity , Apoptosis , Cellular Senescence , Cell Cycle , Cell Line, Tumor , Necrosis , Organometallic Compounds/chemical synthesis , Organometallic Compounds/toxicity , RNA, Messenger/metabolism , LigandsABSTRACT
Two novel sterically hindered cisplatin derivatives with the ligand L=NH(2)C(CH(2)CH(2)COOH)(3) were prepared: cis-PtCl(2)L(2) and cis-PtCl(2)L(NH(3)). The starting compound for the syntheses was NH(2)C(CH(2)CH(2)COOtBu)(3), also known as a building block for dendrimers. cis-PtCl(2)L(2) was prepared from K(2)PtCl(4) in an unusual two-phase reaction in water-chloroform, followed by deprotection of the tert-butyl protective groups with formic acid to yield a water-soluble complex. The mixed-ligand compound cis-PtCl(2)L(NH(3)) was prepared from [PPh(4)][PtCl(3)(NH(3))] in methanol, with subsequent deprotection in formic acid. DNA-binding properties of the two compounds were investigated using the model base guanosine-5'-monophosphate (5'-GMP) and pBR322 plasmid DNA. While cisplatin [cis-PtCl(2)(NH(3))(2)] induced an unwinding of 12 degrees in pBR322 plasmid DNA, cis-PtCl(2)L(NH(3)) induced only 3 degrees unwinding, which is indicative of a monofunctional binding mode. Remarkably, cis-PtCl(2)L(2) did not induce any distortion in plasmid DNA, which strongly suggests that the compound does not bind to DNA. Test reactions with 5'-GMP, monitored by 1H and 195Pt NMR, confirmed that cis-PtCl(2)L(2) is unable to bind to DNA, whereas cis-PtCl(2)L(NH(3)) binds only one nucleotide. Apparently, binding of platinum to nucleotides at the coordination site cis with respect to the ligand L is prevented by steric crowding. Thus, cis-PtCl(2)L(NH(3)) must bind DNA monofunctionally at the trans position. Besides, both compounds have a chloride replaced by one of the carboxylate arms, forming a a seven-membered chelate ring. In theory, cis-PtCl(2)L(2) could also form a second chelate ring, but this was not observed.
Subject(s)
Carboxylic Acids/chemistry , Cisplatin/analogs & derivatives , Cisplatin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Death/drug effects , Cisplatin/chemical synthesis , DNA/metabolism , DNA/ultrastructure , Guanosine Monophosphate/metabolism , Humans , Ligands , Magnetic Resonance Spectroscopy , Plasmids/genetics , Plasmids/metabolism , Plasmids/ultrastructure , Tumor Cells, CulturedABSTRACT
Trans-[PtCl(2)(N,N-dimethylamine)(isopropylamine)] is a novel trans-platinum compound that shows cytotoxic activity in several cisplatin resistant cell lines. The aim of this paper was to analyse, by means of molecular cell biology techniques and total reflection X-ray fluorescence (TXRF), the cytotoxic activity, the induction of apoptosis, the cellular uptake and the DNA binding of trans-[PtCl(2)(N,N-dimethylamine)(isopropylamine)] in the cisplatin resistant cell line A2780cisR. The results show that this drug is more cytotoxic and induces a higher amount of apoptotic cells than cisplatin in A2780cisR cells. However, the intracellular accumulation and extent of binding to DNA of trans-[PtCl(2)(N,N-dimethylamine)( isopropylamine)] is lower than that of cis-DDP. Moreover, trans-[PtCl(2)(N,N-dimethylamine)(isopropylaminae)] is partially inactivated by intracellular levels of glulathione. The result suggest that circumvention of ciplatin resistance by trans-[PtCl(2)(N,N-dimethylamine)(isopropylamine)] in A2780cisR cells might be related with the ability of this drug to induce apoptosis.
ABSTRACT
The discovery in the 1990s of several trans-Pt complexes with in vitro and in vivo activity against tumor cells sensitive and/or resistant to cisplatin has forced the re-evaluation of the structure-activity relationships for platinum antitumor drugs. Because the determinant factors of cytotoxic activity of trans-platinum complexes do not follow the same patterns as those found for cisplatin and its analogues, the differences in cellular and biochemical pharmacology between trans-platinum antitumor complexes and cisplatin might be systematically exploited to design novel trans-platinum complexes with a clinical profile complementary to that of cisplatin and related analogues. Therefore, there may exist a novel molecular rationale for new platinum antitumor drugs development in the twenty-first century.
Subject(s)
Antineoplastic Agents/therapeutic use , Organoplatinum Compounds/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , DNA/metabolism , DNA Adducts/chemistry , DNA Adducts/metabolism , Humans , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/metabolism , Structure-Activity RelationshipABSTRACT
We report here the X-ray structure of cytotoxic trans-¿PtCl(2)(dimethylamine)(isopropylamine). This trans-platinum compound crystallizes in the monoclinic system, with Z = 8, in the spatial group C2/c with unit cell parameters a = 19.862(17) A, b = 6. 581(3) A, c = 18.563(3) A, alpha = 90 degrees, beta = 119.16(3) degrees, gamma = 90 degrees, V = 2119(2) A(3), rho = 2.321 Mg/m(3), R = 0.0505, and R(w) = 0.1166 on the basis of 2339 independent reflections. To our knowledge this is the first report of the crystal structure of a biologically active trans-platinum compound containing different aliphatic amines. The DNA binding mode of trans-¿PtCl(2)(dimethylamine)(isopropylamine) may be a consequence of the spatial disposition of the dimethylamine and isopropylamine ligands around the trans-Pt(II) center. We have found that trans-¿PtCl(2)(dimethylamine)(isopropylamine) readily forms DNA interstrand cross-links. In addition, the compound shows binding affinity toward alternating purine-pyrimidine sequences and inhibits the B-Z transition. These particular DNA binding properties might be related to the capacity of trans-¿PtCl(2)(dimethylamine)(isopropylamine) for inducing some selective killing in a H-ras overexpresssing cell line.
Subject(s)
Antineoplastic Agents/chemistry , Cross-Linking Reagents/chemistry , DNA/chemistry , Organoplatinum Compounds/chemistry , Circular Dichroism , Crystallography, X-Ray , DNA, Superhelical/chemistry , Kinetics , Polydeoxyribonucleotides/chemistry , Sodium Chloride/chemistryABSTRACT
The synthesis and chemical characterization of three new transplatinum complexes of structural formula trans-[PtCl(2)(amine)(isopropylamine)] (amine = n,n-dimethylamine, propylamine, and butylamine), 1-3, are described. Cytotoxicity tests in tumor cell lines sensitive to cis-DDP (Jurkat, Hela, and Vero) and also in tumor cell lines overexpressing ras oncogenes and resistant to cis-DDP (HL-60 and Pam 212-ras) show that complexes 1 and 3 have higher cytotoxic activity than cisplatin. Moreover, these two trans-Pt(II) complexes kill Pam 212-ras cells through apoptosis induction. These results suggest that trans-PtCl(2) complexes with asymmetric aliphatic amines may be considered a new class of biologically active trans-platinum drugs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Genes, ras , Organoplatinum Compounds/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Transformed , Chlorocebus aethiops , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Inhibitory Concentration 50 , Jurkat Cells , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Tumor Cells, Cultured , Vero CellsABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Palladium/chemistry , Platinum/chemistry , Thiosemicarbazones/chemistry , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/pharmacology , Apoptosis/drug effects , Cell Transformation, Neoplastic/genetics , Genes, ras/drug effects , HumansABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cisplatin/pharmacology , Genes, ras , Thiosemicarbazones , Animals , Cell Line , Dimerization , Drug Resistance, Neoplasm/genetics , Keratinocytes/drug effects , MiceABSTRACT
Hitherto, it has been generally accepted as a paradigm of the biochemical pharmacology of platinum antitumor drugs that a cis configuration of the leaving groups is necessary for antitumor activity of platinum compounds. However, it has been recently observed that certain trans-platinum complexes have both in vitro and in vivo antitumor activity. We previously reported the synthesis, characterization and cytotoxic activity against ras-transformed cells of several trans-[PtCl2LL'] complexes where L and L' are asymmetric aliphatic amines (L = dimethylamine and butylamine, L' = isopropylamine). The results reported in this paper show that the compounds trans-[PtCl2(isopropylamine)(dimethylamine)] and trans-[PtCl2(isopropylamine)(butylamine)] kill Pam 212-ras cisplatin resistant cells through apoptosis induction. Moreover, Western blot data show that both compounds inhibit overexpression of H-ras oncogene in Pam 212-ras cells. Altogether, these data indicate that, in contrast with cis-DDP, the apoptotic activity of these novel trans-Pt(II) compounds in ras-transformed cells is associated with their ability to abolish ras-overexpression.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Genes, ras/drug effects , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/genetics , Cell Line, Transformed/drug effects , Cells, Cultured , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Keratinocytes/drug effects , Keratinocytes/pathology , Mice , Oncogene Protein p21(ras)/drug effects , Oncogene Protein p21(ras)/genetics , Organoplatinum Compounds/chemistryABSTRACT
The reaction of platinum salts with bis(naphthalimide), compound 1, yielded two Pt-bis(naphthalimide) complexes, compounds 2 and 3 which differ from each other in their leaving groups being 1,1-cyclobutane dicarboxylate or chloride, respectively. The testing of the cytotoxic activity of compounds 2 and 3 against several tumor cell lines indicated that both compounds may be endowed with important antineoplastic properties since they circumvent cisplatin resistance. At similar rates of DNA platination (r(b) = 0.025), compounds 2 and 3 unwind supercoiled pUC8 DNA by (48 +/- 2) degrees. Altogether, these data suggest (i) that the cytotoxic activity of compounds 2 and 3 may be due to a combined effect of platination and intercalation and (ii) that the bis(naphthalimide) ligand is a suitable "carrier" that favors DNA targeting by cis-Pt(II) centers.
Subject(s)
1-Naphthylamine/metabolism , DNA, Neoplasm/metabolism , Intercalating Agents/chemistry , Platinum/metabolism , 1-Naphthylamine/chemistry , Animals , Cells, Cultured , DNA, Neoplasm/chemistry , Magnetic Resonance Spectroscopy , Mice , Platinum/chemistry , Platinum/pharmacology , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Organometallic Compounds/pharmacology , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cisplatin/pharmacology , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , DNA, Superhelical/chemistry , DNA, Superhelical/drug effects , Dimerization , Drug Resistance , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mice , Nucleic Acid Conformation , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Cisplatin/toxicity , Cross-Linking Reagents/chemistry , Organometallic Compounds/chemistry , Organoplatinum Compounds/chemistry , Thiosemicarbazones/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Survival/drug effects , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/toxicity , Doxorubicin/toxicity , Drug Resistance, Neoplasm , Etoposide/toxicity , HL-60 Cells , HeLa Cells , Humans , Indicators and Reagents , Jurkat Cells , Nuclear Magnetic Resonance, Biomolecular , Organometallic Compounds/chemical synthesis , Organometallic Compounds/toxicity , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/toxicity , Plasmids/drug effects , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/toxicity , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents , Cisplatin/pharmacology , DNA/metabolism , Organometallic Compounds , Thiosemicarbazones , Thiosemicarbazones/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Line , Cell Survival/drug effects , Circular Dichroism , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/metabolism , Cross-Linking Reagents/pharmacology , Crystallography, X-Ray , DNA/chemistry , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Nucleic Acid Conformation , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Organometallic Compounds/metabolism , Organometallic Compounds/pharmacology , Rats , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/metabolism , Thiosemicarbazones/pharmacology , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , DNA/chemistry , Nucleosides/chemistry , Platinum/chemistry , Spermine/chemistry , Cell Division/drug effects , Circular Dichroism , Humans , Isotopes , Magnetic Resonance Spectroscopy/methods , Nucleic Acid Denaturation , Protons , Spectrophotometry, Infrared , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , Diminazene/analogs & derivatives , Platinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Circular Dichroism , DNA Adducts/chemistry , DNA, Neoplasm/chemistry , Diminazene/chemical synthesis , Diminazene/chemistry , Diminazene/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Nucleic Acid Conformation/drug effects , Platinum Compounds/chemical synthesis , Platinum Compounds/chemistry , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Dipyridamole/analogs & derivatives , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/pathology , Cell Division/drug effects , Crystallization , Crystallography, X-Ray , DNA/chemistry , DNA/drug effects , DNA Damage/drug effects , Dipyridamole/chemical synthesis , Dipyridamole/chemistry , Dipyridamole/pharmacology , Humans , Hydrogen Bonding , Leukemia, Promyelocytic, Acute/pathology , Molecular Conformation , Molecular Structure , Nucleic Acid Conformation/drug effects , Organoplatinum Compounds/chemical synthesis , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Organoplatinum Compounds/chemistry , Platinum/chemistry , Spermidine/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Division/drug effects , Circular Dichroism , DNA/chemistry , DNA/drug effects , Electrophoresis, Agar Gel , Escherichia coli/drug effects , Female , Humans , Leukemia/drug therapy , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Plasmids/chemistry , Plasmids/drug effects , Platinum/pharmacology , Spectrophotometry, Ultraviolet , Spermidine/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Palladium/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Cell Division/drug effects , Circular Dichroism , Crystallography, X-Ray , DNA, Circular/chemistry , DNA, Circular/drug effects , DNA, Circular/metabolism , Electrophoresis, Agar Gel , Humans , Leukemia/pathology , Magnetic Resonance Spectroscopy , Molecular Structure , Nucleic Acid Conformation/drug effects , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Palladium/metabolism , Palladium/pharmacology , Plasmids , Spectrophotometry, Infrared , Tumor Cells, CulturedABSTRACT
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.