Francesco P. Intini

Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent

The biological activity of cis and trans complexes of formula [PtCl2(HN = C(OMe)Me)2] has been investigated. The iminoether ligands can have either E or Z configuration about the C = N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumor activity for the complex with trans geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same trans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a trans platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the trans-isomer in the amine complexes, are instead greater for the trans- than for the cis- isomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Trans-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis- platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new trans platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.

Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug

The new platinum(IV) complex cis,trans,cis-[PtCl2(CH3COO)2-(NH3)(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with “conventional” cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).

In vitro and in vivo antitumour activity and cellular pharmacological properties of new platinum–iminoether complexes with different configuration at the iminoether ligands

In order to widen our knowledge on antitumour trans-[PtCl2(iminoether)2] complexes, we have synthesised two new derivatives, trans-[PtCl2¿E-HN = C(OEt)Me¿2] (1) and trans-[PtCl2¿Z-HN = C(OEt)Me¿2] (2), which differ in the configuration of the iminoether ligands. Isomer 1 showed an in vitro cytotoxicity similar to that of cisplatin in a panel of human tumour cell lines (mean IC50 = 8 and 7.7 microM, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 microM). Both 1 and 2 isomers overcame cisplatin resistance of ovarian cancer cell line A2780/Cp8. In agreement with the n-octanol/saline partition ratios, intracellular platinum content (and DNA platination) after a 2-h exposure to equimolar drug concentrations was in the order 1 > 2 >> cisplatin, thus indicating that substitution of imminoethers for ammines determines a major lipophilicity and cellular uptake of the platinum drug. Both 1 and 2 showed a major toxic effect towards an excision repair-defective Drosophila strain, thus indicating cellular DNA as cytotoxic target. Finally, both 1 and 2 were active in vivo against the murine P388 system, but, contrary to the in vitro activity, isomer 2 was slightly more active than 1. On the whole, the results confirm the antitumour activity of trans-[PtCl2(iminoether)2] complexes, and indicate that the configuration of the iminoether ligands may affect the pharmacological properties of this class of complexes.

Four-versus five-co-ordination in palladium(II) and platinum(II) complexes containing 2,9-dimethyl-1,10-phenanthroline (dmphen). Crystal structures of [PtCl2(dmphen)] and [Pt(η2-C2H4)Cl2(dmphen)]

The four-co-ordinate complexes with 2,9-dimethyl-1,10-phenanthroline [MX2(dmphen)](M = Pt, X2= Cl21, ClBr 2, Br23, or I24; M = Pd, X2= Cl25, ClBr 6, Br27 or I28) have been prepared for the first time. The crystal structure of [PtCl2(dmphen)]1, has been determined by X-ray diffraction methods. The complex has a square-planar geometry around the metal and the steric interaction between the methyl groups of dmphen and the cis chlorine ligands causes a narrowing of the Cl–Pt–Cl angle [85.8(1)°], a displacement of the two chlorine atoms from the N–Pt–N plane [0.286(4) and 0.372(4)A respectively], a bending of the phenanthroline (ca. 17°), and a rotation of the overall ligand plane with respect to the platinum co-ordination plane (ca. 28°). All interligand steric constraints are released in the five-co-ordinate complexes obtained from the four-co-ordinate species by direct uptake of olefins, [M(η2-olefin)X2(dmphen)](olefin = ethylene, a; propene, b; but-1-ene, c; cis-but-2-ene, d; trans-but-2-ene, e; or styrene, f). The structure of [Pt(η2-C2H4)Cl2(dmphen)]1a, has been determined by X-ray diffraction methods. The complex has a trigonal-bipyramidal geometry around the Pt atom; the phenanthroline ligand and the olefinic carbons occupy the equatorial plane while the two chlorine atoms are in axial positions. Bond distances and angles are similar to those found in other five-co-ordinate complexes of platinum(II). The rate of uptake of olefin by the four-co-ordinate complexes, the equilibrium constant (Kf) of the formation reaction [MX2(dmphen)]+ olefin ⇌[M(η2-olefin)X2(dmphen)], and the activation energy for olefin rotation in the five-co-ordinate complexes have been measured for different olefins and halogen ions. The uptake, in chloroform, takes place in a one-step process and the reaction rate increases by a factor of 104 going from the chloro 1 to the iodo 4 complex. The equilibrium constant for the formation reaction decreases by a factor of 103 going from ethylene to trans-but-2-ene and increases by a factor of 102 going from the chloro 1 to the iodo 4 species. The activation energy for olefin rotation (ethylene and propene)(ca. 20.5 kcal mol–1) is higher than any reported value for platinum complexes and does not appear to depend upon the nature of the halogen atoms.

Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine

Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.

Novel antitumor cisplatin and transplatin derivatives containing 1-methyl-7-azaindole: synthesis, characterization, and cellular responses.

The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag.

Platinum complexes with imino ethers or cyclic ligands mimicking imino ethers: synthesis, in vitro antitumour activity, and DNA interaction properties

Both trans- and cis-[PtCl2(NH3)(L)] compounds have been synthesized, L representing either the imino ether HN=C(OMe)Me having a Z or E configuration at the C=N double bond, or the cyclic ligands % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! % MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8YjY-vipgYlH8Gipec8Eeeu0x % Xdbba9frFj0-OqFfea0dXdd9vqai-hGuQ8kuc9pgc9q8qqaq-dir-f % 0-yqaiVgFr0xfr-xfr-xb9adbaqaaeGaciGaaiaabeqaamaabmabaa % GcbaWaaKraaeaacaqGobGaaeypaiaaboeacaqGOaGaae4taiaab2ea % caqGLbGaaeykaiaaboeacaqGibWaaSbaaSqaaiaabkdaaeqaaOGaae % 4qaiaabIeadaWgaaWcbaGaaeOmaaqabaGccaqGdbaaleaaaOGaayzd % SdGaaeisamaaBaaaleaacaqGYaaabeaaaaa!47FE!

Platinum amides from platinum nitriles: X-ray crystal structure of trans-dichloro-bis(1-imino-1-hydroxy-2,2-dimethylpropane)platinum(II)

{\overbrace {{\text{N = C(OMe)CH}}_{{\text{2}}} {\text{CH}}_{{\text{2}}} {\text{C}}}^{} }{\text{H}}_{{\text{2}}}