Synthesis of new heteroscorpionate iridium(I) and iridium(III) complexes.

The reactivity of different heteroscorpionate ligands based on bis(pyrazol-1-yl)methane, with different iridium-(i) and -(iii) precursors is reported. The reaction of the heteroscorpionate lithium salts "Li(bdmpza)", [bdmpza = bis(3,5-dimethylpyrazol-1-yl)acetate], "Li(bdmpzdta)" [bdmpzdta = bis(3,5-dimethylpyrazol-1-yl)dithioacetate] and "Li(S)-mbpam" [(S)-mbpam = (S)-(-)-N-α-methylbenzyl-2,2-bis(3,5-dimethylpyrazol-1-yl)acetamidate] with 1 equivalent of [IrCl3(THF)3] in THF for 18 h affords high yields of neutral and anionic heteroscorpionate chloride iridium complexes [IrCl2(bdmpza)(THF)] (), [Li(THF)4][IrCl3(bdmpzdta)] () and [IrCl2{(S)-mbpam})(THF)] (). Solution of complex in acetonitrile at room temperature leads to complex [IrCl2{(S)-mbpam})(NCCH3)] (). Complexes and were isolated as enantiopure compounds. The reaction of the lithium salt "Li(bdmpza)" with [IrCl(η(4)-CH2[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]CH2)]2 in THF for 18 h gave the Ir(i) complex [Ir(bdmpza)(η(4)-CH2[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]CH2)] (). The reaction of complex with CO (2 atm) at room temperature leads to a new complex of Ir(iii), [Ir(bdmpza)(k(2)-CH2C(Me)[double bond, length as m-dash]C(Me)CH2)(CO)] (). Treatment of heteroscorpionate ligand precursors "Li(bdmpza)" and "Li(bdmpzdta)" with [IrCp*Cl2]2 in THF yielded the iridium(iii) complexes [Ir2Cp*2Cl2(bdmpzx)] (x = a , x = dta ). These complexes have helical chirality due to the demands of the fixed pyrazole rings. The stereoisomerism and the self-assembly processes of these helicates have been studied in some detail in solution by NMR spectroscopy and in the solid state by X-ray diffraction. Mixtures of M- and P-handed enantiomers were obtained. Complex undergoes a decarboxylation process initiated by the HCl generated in the previous step leading to the known ionic complex [IrClCp*(bdmpm)][IrCl3Cp*] [bdmpm = bis(3,5-dimethylpyrazol-1-yl)methane] (). The structures of the complexes were determined by spectroscopic methods and the X-ray crystal structures of , , and were also established.

Lewis base character of the phosphorus atom in phosphanido-niobocene complexes. Synthesis of new early-early homo- and heterobimetallic entities.

The reaction of phosphanido complexes [Nb(η(5)-C(5)H(4)SiMe(3))(2)(L)(PPh(2))] [L = CO (1), CNXylyl (2)] with early transition metal halides in high oxidation states has been carried out. New bimetallic niobocene complexes [{Nb(η(5)-C(5)H(4)SiMe(3))(2)(L)}(µ-PPh(2))(MCl(5))] [M = Nb, L = CO (3), L = CNXylyl (4); M = Ta, L = CO (5), L = CNXylyl (6)] have been successfully synthesized by the reaction with [MCl(5)](2) (M = Nb or Ta). In a similar way [{Nb(η(5)-C(5)H(4)SiMe(3))(2)(L)}(µ-PPh(2))(MCl(4))] [M = Ti, L = CO (13), CNXylyl (14); M = Zr, L = CO (15), CNXylyl (16)] were synthesized using MCl(4) (M = Ti or Zr). Solutions of complexes 4-6 in chloroform produced new ionic derivatives [Nb(η(5)-C(5)H(4)SiMe(3))(2)(P(H)Ph(2))(L)] [MCl(6)] [M = Nb, L = CO (7), L = CNXylyl (8); M = Ta, L = CO (9), L = CNXylyl (10)]. Ionic complexes [Nb(η(5)-C(5)H(4)SiMe(3))(2)(P(Cl)Ph(2))(L)] [NbCl(4)O(thf)] [L = CO (11), CNXylyl (12)] were formed from solutions in thf - rapidly in the case of 3 but more slowly for 4. New heterometallic complexes [Nb(η(5)-C(5)H(4)SiMe(3))(2)(L)(µ-PPh(2)){(Ti(η(5)-C(5)R(5))Cl(3)}] [R = H, L = CO (17), CNXylyl (18); R = CH(3), L = CO (19), CNXylyl (20)] were synthesized by the reaction of 1 or 2 with [Ti(η(5)-C(5)R(5))Cl(3)] (R = H or CH(3)). All of these compounds were characterized by IR and multinuclear NMR spectroscopy, and the molecular structures of 9 and 12 were determined by single-crystal X-ray diffraction.

Direct synthesis of NNN-donor enantiopure scorpionate ligands by an efficient diastereoselective nucleophilic addition to imines.

New enantiopure imines (1-9) with a chiral substrate to control the stereochemistry of a newly created stereogenic center have been synthesized by reaction of the commercially available (1R)-(-)-myrtenal and different primary amines. The diastereomerically enriched lithium-scorpionate compounds [Li(κ(3)-mobpza)(THF)] (10) (mobpza = N-p-methylphenyl-(1R and 1S)-1-[(1R)-6,6-dimethylbicyclo[3.1.1]-2-hepten-2-yl]-2,2-bis(3,5-dimethylpyrazol-1-yl)ethylamide), [Li(κ(3)-mobpza)(THF)] (11) (mobpza = N-p-methoxyphenyl-(1R and 1S)-1-[(1R)-6,6-dimethylbicyclo[3.1.1]-2-hepten-2-yl]-2,2-bis(3,5-dimethylpyrazol-1-yl)ethylamide), [Li(κ(3)-fbpza)(THF)] (12) (fbpza = N-p-fluorophenyl-(1R and 1S)-1-[(1R)-6,6-dimethylbicyclo[3.1.1]-2-hepten-2-yl]-2,2-bis(3,5-dimethylpyrazol-1-yl)ethylamide), and [Li(κ(3)-clbpza)(THF)] (13) (clbpza = N-p-chlorophenyl-(1R and 1S)-1-[(1R)-6,6-dimethylbicyclo[3.1.1]-2-hepten-2-yl]-2,2-bis(3,5-dimethylpyrazol-1-yl)ethylamide) were obtained by a diastereoselective 1,2-addition of an organolithium reagent to imines in good yield and with good diastereomeric excess (ca. 80%). The complexes [LiCl(κ(2)-R,R-fbpzaH)(THF)] (14) and [LiCl(κ(2)-R,R-clbpzaH)(THF)] (15) were obtained in enantiomerically pure form by the treatment of THF solutions of 12 or 13 with NH(4)Cl. The enantiomerically pure amines (R,R-mbpzaH) (16), (R,R-mobpzaH) (17), (R,R-fbpzaH) (18), and (R,R-clbpzaH) (19) were obtained by hydrolysis of the lithium-scorpionate compounds 10-13 with H(2)O. The lithium compound 12 was reacted with [TiCl(4)(THF)(2)] or [ZrCl(4)] to give the enantiopure complexes [MCl(3)(κ(3)-R,R-fbpza)] [M = Ti (20), Zr (21)]. The amine compound 18 reacted with [MX(4)] (M = Ti, X = O(i)Pr, OEt; M = Zr; X = NMe(2)) to give the complexes [MX(3)(κ(3)-R,R-fbpza)] (22-24). The reaction of Me(3)SiCl with [Zr(NMe(2))(3)(κ(3)-R,R-fbpza)] (24) in different molar ratios led to the halide-amide-containing complexes [ZrCl(NMe(2))(2)(κ(3)-R,R-fbpza)] (25) and [ZrCl(2)(NMe(2))(κ(3)-R,R-fbpza)] (26) and the halide complex 21. The isolation of only one of the three possible diastereoisomers of complexes 25 and 26 revealed that chiral induction from the ligand to the zirconium center took place. The structures of these compounds were elucidated by (1)H and (13)C{(1)H} NMR spectroscopy, and the X-ray crystal structures of 5, 12, 14, 15, and 24 were also established.

New complexes of zirconium(IV) and hafnium(IV) with heteroscorpionate ligands and the hydrolysis of such complexes to give a zirconium cluster.

A series of zirconium and hafnium heteroscorpionate complexes have been prepared by the reaction of MCl4 (M = Zr, Hf) with the compounds [[Li(bdmpza)(H2O)](4)] [bdmpza = bis(3,5-dimethylpyrazol-1-yl)acetate], [[Li(bdmpzdta)(H2O)](4)] [bdmpzdta = bis(3,5-dimethylpyrazol-1-yl)dithioacetate], and (Hbdmpze) [bdmpze = 2,2-bis(3,5-dimethylpyrazol-1-yl)ethoxide] (the latter with the prior addition of Bu(n)Li). Under the appropriate experimental conditions, mononuclear complexes, namely, [MCl3(kappa3-bdmpzx)] [x = a, M = Zr (1), Hf (2); x = dta, M = Zr (3), Hf (4); x = e, M = Zr (5), Hf (6)], and dinuclear complexes, namely, [[MCl2(mu-OH)(kappa3-bdmpzx)]2] [x = a, M = Zr (7), Hf (8); x = dta, M = Zr (9); x = e, M = Zr (10)], were isolated. A family of alkoxide-containing complexes of the general formula [ZrCl2(kappa3-bdmpzx)(OR)] [x = a, R = Me (11), Et (12), iPr (13), tBu (14); x = dta, R = Me (15), Et (16), iPr (17), tBu (18); x = e, R = Me (19), Et (20), (i)Pr (21), (t)Bu (22)] was also prepared. Complexes 11-14 underwent an interesting hydrolysis process to give the cluster complex [Zr6(mu3-OH)8(OH)8(kappa2-bdmpza)8] (23). The structures of these complexes have been determined by spectroscopic methods, and the X-ray crystal structures of 7, 8, and 23 were also established.

Preparation of new monoanionic "scorpionate" ligands: synthesis and structural characterization of titanium(IV) complexes bearing this class of ligand.

The preparation of new "scorpionate" ligands in the form of the lithium derivatives [(Li(bdmpzdta)(H(2)O))(4)] (1) [bdmpzdta = bis(3,5-dimethylpyrazol-1-yl)dithioacetate], [Li(bdphpza)(H(2)O)(THF)] (2) [bdphpza = bis(3,5-diphenylpyrazol-1-yl)acetate], and [Li(bdphpzdta)(H(2)O)(THF)] (3) [bdphpzdta = bis(3,5-diphenylpyrazol-1-yl)dithioacetate] has been carried out. Furthermore, a series of titanium complexes has been prepared by reaction of TiCl(4)(THF)(2) with the lithium reagents [(Li(bdmpza)(H(2)O))(4)] (4) [bdmpza = bis(3,5-dimethylpyrazol-1-yl)acetate] and 1. Under the appropriate experimental conditions neutral complexes, namely [TiCl(3)(kappa(3)-bdmpza)] (5), [TiCl(3)(kappa(3)-bdmpzdta)] (6), and [TiCl(2)(kappa(2)-bdmpzdta)(2)] (7), and cationic complexes, namely [TiCl(2)(THF)(kappa(3)-bdmpza)]Cl (8) and [TiCl(2)(THF)(kappa(3)-bdmpzdta)]Cl (9), were isolated. Complexes 8 and 9 undergo an interesting nucleophilic THF ring-opening reaction to give the corresponding alkoxide-containing species [TiCl(2)(kappa(3)-bdmpza)(O(CH(2))(4)Cl)] (10) and [TiCl(2)(kappa(3)-bdmpzdta)(O(CH(2))(4)Cl)] (11). A family of alkoxide-containing complexes of general formulas [TiCl(2)(kappa(3)-bdmpza)(OR)] [R = Me (12); R = Et (14); R = (i)Pr (16); R = (t)Bu (18)] and [TiCl(2)(kappa(3)-bdmpzdta)(OR)] [R = Me (13); R = Et (15); R = (i)Pr (17)] was also prepared. The structures of these complexes have been determined by spectroscopic methods, and in addition, the X-ray crystal structures of 3, 7, 10, and 11 were also established.

Combined effect of platination and intercalation upon DNA binding of novel cytotoxic Pt-bis(naphthalimide) complexes.

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.

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.

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.

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) 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.