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Research has been conducted on macrocyclic DOTA (DOTA=1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid) complexes. The structural changes occurring in Ln(DOTA) family with the decrease of lanthanide(III) ionic radius have been investigated via the use of NMR solution studies, and the results are reported.

The reactions of the nitrile complexes cis- and trans-[PtCl2(NCR)2] (R = Me, Et, CH2Ph, Ph) with an excess of ethanethiol, EtSH, in the presence of a catalytic amount of n-BuLi in tetrahydrofuran (THF), afforded in good yield the bis-imino thioether derivatives cis-[PtCl2{E-N(H)═C(SEt)R}2] (R = Me (1), Et (2), CH2Ph (3), Ph (4)) and trans-[PtCl2{E-N(H)═C(SEt)R}2] (R = Me (5), Et (6), CH2Ph (7), Ph (8)). The imino thioether ligands assumed the E configuration corresponding to a cis addition of the thiol to the nitrile triple bond. The spectroscopic properties of these complexes have been reported along with the molecular structures of 1, 2, and 7 as established by X-ray crystallography which indicated that these compounds exhibit square-planar coordination geometry around the platinum center. Four N-H···Cl intermolecular contacts (N-H···Cl ca. 2.5-2.7 Å) between each chlorine atom and the N-H proton of the imino thioether ligand gave rise to "dimers" Pt2Cl4L4 (L = imino thioether) formed by two PtCl2L2 units. The cytotoxic properties of these new platinum(II) complexes were evaluated against various human cancer cell lines. Among all derivatives, trans-[PtCl2{E-N(H)═C(SEt)CH2Ph}2] showed the greatest in vitro cytotoxic activity being able to decrease cancer cell viability roughly 3-fold more effectively than cisplatin.

The thermodynamics of the complexation between uranium(VI) and acetate in dimethyl sulfoxide (DMSO) was studied at 298 K in an ionic medium of 0.1 mol dm(-3) tetrabutyl ammonium perchlorate. The results show that the uranyl ion forms three strong successive mononuclear complexes with acetate. The complexes, both enthalpically and entropically stabilized, are significantly more stable in DMSO than in water. This feature can be ascribed to the weak solvation of acetate in DMSO. The thermodynamic parameters for the formation of the uranium(VI) complexes with acetate in DMSO are compared with those with ethylenediamine in the same solvent. The difference between the two ligand systems reveals that, for the complexation reactions involving charge neutralization, the reorganization of the solvent gives a very important contribution to the overall complexation energetics. The coordination mode of acetate in the uranyl complexes and the changes of the solvation sphere of UO(2)(2+) upon complexation were investigated by FT-IR spectroscopy in DMSO and in acetonitrile/DMSO mixtures. In addition, DFT calculations were performed to provide an accurate description of the complexation at the molecular level. The experimental and calculated results suggest that acetate is solely bidentate to UO(2)(2+) in the 1:1 and 1:3 complexes but mono- and bidentate in the 1:2 complexes. The DFT calculations also indicate that the medium effects must always be taken into account in order to gain accurate information on the complex formation in solution. In fact, the relative stability of the reaction products changes markedly when the DFT calculations are carried out in vacuum or in DMSO solution.

The coordination abilities of the novel N,N'-diphosphino-silanediamine ligand of formula SiMe(2)(NtolPPh(2))(2) (SiNP, 1) have been investigated toward rhodium, and the derivatives [RhCl(SiNP)](2) (2), [Rh(SiNP)(COD)][BF(4)] (3), and Rh(acac)(SiNP) (4) have been synthesized. The stability of the dinuclear frame of [RhCl(SiNP)](2) (2) toward incoming nucleophiles has been shown to be dependent on their π-acceptor ability. Indeed, the mononuclear complexes RhCl(SiNP)(L) (L = CO, 5; CN(t)Bu, 6) have been isolated purely and quantitatively upon reaction of 2 with CO and CN(t)Bu, respectively. Otherwise, PPh(3) and RhCl(SiNP) equilibrate with Rh(Cl)(SiNP)(PPh(3)) (7). Carbon electrophiles such as MeI and 3-chloro-1-proprene afforded the oxidation of rhodium(I) to rhodium(III) and the formation of RhCl(2)(η(3)-C(3)H(5))(SiNP) (8) and Rh(Me)(I)(SiNP)(acac) (10), respectively. The methyl derivative 10 is thermally stable and does not react either with CO or with CN(t)Bu even in excess. Otherwise, RhCl(2)(η(3)-C(3)H(5))(SiNP) (8) is thermally stable but reacts with CO, affording 3-chloro-1-proprene and RhCl(SiNP)(CO) (5). Finally, upon reaction of Rh(acac)(SiNP) (4) and 3-chloro-1-proprene, RhCl(acac)(η(1)-C(3)H(5))(SiNP) (9a) and [Rh(acac)(η(3)-C(3)H(5))(SiNP)]Cl (9b) could be detected at 233 K. At higher temperatures, 9a and 9b smoothly decompose, affording the dinuclear derivative [RhCl(SiNP)](2) (2) and the CC coupling product 3-allylpentane-2,4-dione.

The reactions of cyclopropylamine, cyclopentylamine, and cyclohexylamine with trans-[PtCl2(NCMe)2] afforded the bis-cationic complexes trans-[Pt(amine)2(Z-amidine)2]2+[Cl-]2, 1-3. The solution behavior and biological activity have been studied in different solvents (DMSO, water, polyethylene glycol (PEG 400), and polyethylene glycol dimethyl ether (PEG-DME 500)). The biological activity was strongly influenced by the cycloaliphatic amine ring size, with trans-[Pt(NH2CH(CH2)4CH2)2{N(H) horizontal lineC(CH3)N(H)CH(CH2)4CH2}2]2+[Cl-]2 (3) being the most active compound. Complex 3 overcame both cisplatin and MDR resistance, inducing cancer cell death through p53-mediated apoptosis. Alkaline single-cell gel electrophoresis experiments indicated direct DNA damage, reasonably attributable to DNA adducts of trans-[PtCl(amine)(Z-amidine)2][Cl] species, which can evolve to produce disruptive and nonrepairable lesions on DNA, thus leading to the drug-induced programmed cancer cell death. Preliminary in vivo antitumor studies on C57BL mice bearing Lewis lung carcinoma highlighted that complex 3 promoted a significant and dose-dependent tumor growth inhibition without adverse side effects.

New benzyliminoether derivatives [PtCl2{N(H)=C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups.

The new dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand, [H2B(tzNO2)2]-, has been synthesized in dimethylacetamide solution, using 3-nitro-1,2,4-triazole and KBH4 through careful temperature control, and characterized as its potassium salt. The zinc(II) and cadmium(II) complexes, {M[H2B(tzNO2)2]Cl(H2O)2}, have been prepared by metathesis of [H2B(tzNO2)2]K with ZnCl2 and CdCl2, respectively. The complexes likely contain a metal core in which the ligand is coordinated to the metal ions in the K2-N,N' or K4-N,N',O,O' fashion. A single-crystal structural characterization is reported for the potassium dihydrobis(3-nitro-1,2,4-triazolyl)borate. The potassium salt is polymeric and shows several K...N and K...O interactions.

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.