J.R. Masaguer

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.

Cyclometallated complexes of Pd(II) and Pt(II) with 2-phenylimidazoline

Abstract Cyclometallated complexes of Pd(II) and Pt(II) with 2-phenylimidazoline were synthesized. The complexes were characterized by 1H and 13C NMR spectroscopy, involving the use of COSY-45, HMQC and HMBC techniques, which allow unambiguous assignment of the NMR parameters. An X-ray diffraction study of [Pd(C6H4−C3H5N2)(μ-OAc)]2 confirmed that cyclometallation of the 2-phenylimidazoline ligand had occurred.

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 pHs, 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.

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 and NMR structural analysis of several orthopalladated complexes of substituted benzo-imidazole, -oxazole and -thiazole and study of two polymorphic crystals

Abstract The full assignation of 1 H and 13 C NMR parameters using both homo- and hetero-nuclear two dimensional spectroscopy techniques (COSY, HMQC and HMBC) allows the determination of electronic properties in cyclopalladated complexes obtained by reaction of N -methyl-2-phenylbenzimidazole ( a ), 2-phenylbenzothiazole ( b ) and 2-phenylbenzoxazole ( c ) with palladium salts. The attempts to separate the anti and syn isomers (detected by NMR) led to the formation of two different kinds of crystal for the 2-phenylbenzoxazole palladium complex, 1c (yellow and orange). The X-ray diffraction study of these crystals indicates the formation of two polymorphic phases both in anti disposition.

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.

Synthesis, characterization, and electrochemistry of the mono- and bi-dentate xanthate complexes η5-C5R5Fe(CO)(η1-SC(S)OEt)L and η5-C5R5Fe(η2-S2COEt) L (R = H, Me; L = PBu3, PPh3, P(OEt)3, P(OPh)3)

Abstract The mixed carbonyl-phosphorus ligand monodentate xanthate complexes η 5 -C 5 H 5 Fe(CO)(η 1 -SC(S)OEt)L ( 5a – 5d ), can be conveniently obtained by treatment of the dicarbonyl compound η 5 -C 5 H 5 Fe(CO) 2 (η 1 -SC(S)OEt) ( 1 ) with the appropriate phosphine or phosphite ligand L (PBu 3 , PPh 3 , P(OEt) 3 , p(oPh) 3 ). In contrast, similar reactions between the analogous pentamethylcyclopentadienyl complex η 5 -C 5 Me 5 Fe(CO) 2 (η 1 -SC(S)OEt) ( 2 ) and the same phosphorus ligands L give not only the substituted complexes η 5 -C 5 Me 5 Fe(CO)(η 1 -SC(S)OEt)L ( 6a – 6d ), but also the monocarbonyl-bidentate xanthate complex η 5 -C 5 Me 5 Fe(CO)(η 2 -S 2 COEt) ( 4 ), with the ratio of these two types of products dependent on the ligand L. UV photolysis of the monodentate xanthate series of complexes 5 and 6 gives the complexes η 5 -C 5 R 5 Fe(η 2 -S 2 COEt)L (R = H ( 7a – 7d ); R = Me ( 8a – 8d ). The complexes 5a -– 5d and 6a – 6d undergo one-electron oxidation by an EC mechanism leading to the corresponding bidentate xanthate complexes 7a – 7d and 8a – 8d . For 5c , 5d and 6d formation of the cationic species [η 5 -C 5 R 5 Fe(CO)L] + (R = H and Me) is also observed.

Tetracyanoethylene complexes of monomethylcyclopentadienylcobalt derivatives

Abstract The complexes (MeCp)Co(L)TCNE (L = CO, PPh 3 , P(OMe) 3 , py; MeCp = methylcyclopentadienyl; TCNE = tetracyanoethylene; py = pyridine) have been made. The TCNE acts as a one-electron oxidizing agent, and is σ-bonded to cobalt through a nitrile nitrogen. All the compounds have been characterized by elemental analysis, magnetic susceptibility measurements, and IR, electronic, 1 H NMR, and ESR spectroscopy.

Mono-μ-hydrido complexes of pentamethylcyclopentadienylcobalt

Abstract The complex (η5-C5Me5)Co(CO)2 reacts with Cl2 and with Br2 to give [(η5-C5Me5)CoCl(μ-Cl)]2 and (η5-C5Me5)Co(CO)Br2, respectively. The latter was converted into the dimeric species [(η5-C5Me5CoBr(μ-Br)]2. The reaction of dimeric pentamethylcyclopentadienylcobalt complexes [(η5-C5Me5)CoX(μ-X)]2 (X = Cl, Br, I) with potassium hydroxide gives the mono-μ-hydrido complexes [(η5-C5Me5)CoX]2(μ-H)(μ-X).

Oxidative addition reactions TO Cp′Co(CO)L (Cp′ = C5H4CH3; L = CO, PPh3 and tetracyanoethylene) with XCN (X = Br, I)

Abstract Oxidative addition of XCN (X = Br, I) to Cp′Co(CO)L (L = CO, PPh 3 ) leads to the formation of Cp′CoL(CN)X. The complexes C′ p CoTCNE(L) do not react with XCN.