On the Mechanism of Action of the Antitumor Drug cis-Platin (cis-DDP) and its Second Generation Derivatives

The present article attempts to summarise the elements of the mechanism of action of the antitumor drug cis¯-Platin presented the last few years. Highlights on the discovery, of the drug and the development of it’s second generation derivatives are presented, as well as the ways that cis¯-DDP reacts with biomolecules as DNA and proteins and their models e.g. nucleosides, nucleotides. Also the hydrolysis data are presented for cis¯-DDP and its’ inactive congener trans¯-DDP, as well as for the second generation drug carboplatin. Finally, usefull conclusions are given from this work, pointing out the unanswered questions about the action of cis¯-DDP as well as its differences in action, in comparison with trans¯-DDP

Interaction of Thioamides, Selenoamides, and Amides With Diiodine

We review the results of our work on the iodine interaction with thioamides, selenoamides, and amides. Complexes with (i) “spoke” or “extended spoke” structures, D · I(2) and D · I(2) · I(2), respectively, (D is the ligand donor) (ii) iodonium salts of {[D(2) − I](+)[I(n)](−)} (n = 3, 7) and {[D(2) − I](+)[FeCl(4)](−)} formulae and (iii) disulfides of the categories (a) [D − D], (b) {[D − DH](+)[I(3)](−)} have been isolated and characterized. A compound of formula {[D(2) − I](+)[I(3)](−)[D · I(2)]} containing both types of complexes (i) and (ii) was also isolated. The interaction of diiodine with selenium analogs of the antithyroid drug 6-n-propyl-2-thiouracil (PTU), of formulae RSeU (6-alkyl-2-Selenouracil) results in the formation of complexes with formulae [(RSeU)I(2)]. All these results are correlated with the mechanism of action of antithyroid drugs. Finally, we review here our work on the diiodine interaction with the amides (LO)

A NMR study of the interaction of a three-domain construct of ATP7A with copper(I) and copper(I)-HAH1: the interplay of domains.

ATP7A is a P-type ATPase involved in copper(I) homeostasis in humans. It possesses a long N-terminal tail protruding into the cytosol and containing six copper(I)-binding domains, which are individually folded and capable of binding one copper(I) ion. ATP7A receives copper from a soluble protein, the metallochaperone HAH1. The exact role and interplay of the six soluble domains is still quite unclear, as it has been extensively demonstrated that they are strongly redundant with respect to copper(I) transport in vivo. In the present work, a three-domain (fourth to sixth, MNK456) construct has been investigated in solution by NMR, in the absence and presence of copper(I). In addition, the interaction of MNK456 with copper(I)-HAH1 has been studied. It is proposed that the fourth domain is the preferential site for the initial interaction with the partner. A significant dependence of the overall domain dynamics on the metallation state and on the presence of HAH1 is observed. This dependence could constitute the molecular mechanism to trigger copper(I) translocation and/or ATP7A relocalization from the trans-Golgi network to the plasmatic membrane

The First Metal Complexes of 4,6-diamino-1-hydro-5-hydroxy-pyrimidine-2-thione: Preparation, Physical and Spectroscopic Studies, and Preliminary Antimicrobial Properties

The new complexes [M2O5L2(H2O)2] · H2O (M = Mo, 1; M = W, 2), [RuL2(H2O)2] · H2O (3), [ML3] · xH2O (M = Rh, x = 2, 4; M = Ir, x = 1, 5), [RhL2(PPh3)2](ClO4) · 2H2O (6), [PdL2] · 2H2O (7), [PdL(phen)]Cl · H2O (8), [Re OL2(PPh3)]Cl (9) and [UO2L2] (10) are reported, where LH is 4,6-diamino-1-hydro-5-hydroxy-pyrimidine-2-thione. The complexes were characterized by elemental analyses, physical techniques (molar conductivity, room-temperature magnetic susceptibility), and spectroscopic (IR, Raman, UV/VIS/ligand field, NMR, mass) methods. The ligand L− is in its thione form and behaves as a bidentate chelate with the deprotonated (hydroxyl) oxygen and the nitrogen of one amino group as donor atoms. Oxobridged dinuclear (1, 2) and various mononuclear (3–10) structures are assigned for the complexes in the solid state. The metal ion coordination geometries are octahedral (1–6, 9, 10) or square planar (7, 8). The free ligand LH and complexes 1, 4, 7, and 8 were assayed in vitro for antimicrobial activity against two bacterial and two fungal cultures

Interaction of Cu(II)with His-Val-Gly-Asp and of Zn(II) with His-Val-His, Two Peptides at the Active Site of Cu,Zn-Superoxide Dismutase

His-Val-His and His-Val-Gly-Asp are two naturally occurring peptide sequences, present at the active site of Cu,Zn-superoxide dismutase (Cu,Zn-SOD). We have already studied the interaction of His-Val-His=A (copper binding site) with Cu(II) and of His-Val-Gly-Asp=B (zinc binding site) with Zn(II). As a continuation of this work and for comparison purposes we have also studied the interaction of Zn(II) with His-Val-His and Cu(II) with His-Val-Gly-Asp using both potentiometric and spectroscopic methods (visible, EPR, NMR). The stoichiometry, stability constants and solution structure of the complexes formed have been determined. Histamine type of coordination is observed for/ZnAH/2+, /ZnA/+, /ZnA2H/+ and/ZnA2/ in acidic pH while deprotonation of coordinated water molecules is observed at higher pH. /CUB/ species is characterized by the formation of a macrochelate and histamine type coordination. Its stability results in the suppression of amide deprotonation which occurs at high pH resulting in the formation of the highly distorted from square planar geometry 4N complex/CuBH-3/3

Transition and Group IIB Metal Complexes With “Active Aldehyde” Derivatives of Thiamine

The Zn2+, Cd2+, Hg2+, Co2+ and Ni2+ ions produce zwitterionic type complexes with the ligands (L), 2-(α-hydroxy-benzyl)thiamine=HBT and 2-(α-hydroxy-cyclohexyl-methyl)thiamine = HCMT, of the type MLCl3. The ligands are in the S conformation, the metals are bound to N1, of the pyrimidine moiety of thiamine and the complexes have a trigonally distorted tetrahedral structure, as the crystal structure of the complex Zn(HCMT)Cl3 (orthorombic, a=14.4 b=14.1 c=17.4 β=105.6O V=3392A3 R=13.8%), the one and two dimensional 1H nmr spectra of the Zn2+, Cd2+ and Hg2+ complexes and the electronic spectra of the Co2+ and Ni2+ complexes show. A brief review of the previous techniques (structure of the Hg(HBT)Cl3 complex, IR-Raman spectra, 13C nmr in solution and solid state etc) used to characterize these complexes, is also given here and the proper conclusions drawn

Interactions of Zn(II) Ions with Three His-Containing Peptide Models of Histone H2A

The interactions of Zn(ll) ions with the blocked hexapeptide models -TESHHK-, -TASHHK- and -TEAHHK- of the -ESHH- motif of the C-terminal of historic H2A were studied by using potentiometric and IH-NMR techniques. The first step of these studies was to compare the pKa values of the two His residues inside each hexapeptide calculated by potentiometric or H-NMR titrations. Hereafter, the potentiometric titrations in the pH range 5 11 suggest the formation of several monomeric Zn(ll) complexes. It was found that all hexapeptides bind to Zn(ll) ions initially through both imidazole nitrogens in weakly acidic and neutral solutions forming slightly distorted octahedral complexes. At higher pH values, the combination of potentiometric titrations and one and two dimensional NMR suggested no amide coordination in the coordination sphere of Zn(II) ions. Obviously, these studies support that the -ESHH- sequence of histone H2A is a potential binding site for Zn(II) ions similarly with the Cu(II) and Ni(ll) ions, presented in previous papers

Thermodynamic and Structural Characterization of the Copper(II) Complexes of Peptides Containing Both Histidyl and Aspartyl Residues

Terminally protected pentapeptides with 2 histidines (Ac-HHVGD-NH2 and Ac-HVGDH-NH2) and the terminally free peptides containing both internal aspartyl and C-terminal histidyl residues (FDAH and VIDAH) have been synthesized, and copper(II) complexes studied by potentiometric, UV-Vis, CD, and EPR spectroscopic techniques in solution. Both thermodynamic and spectroscopic data reveal that side chain donor atoms of aspartyl and histidyl residues have a significant contribution to the metal binding affinity of peptide molecules. In the case of terminally protected peptides, the role of the imidazole-N donor functions is reflected in the enhanced stability of the 3N and 4N coordinated copper(II) complexes. The amino and β-carboxylate groups of FDAH and VIDAH create a very effective metal binding site with the (NH2, N−, β-COO−) and (NH2, N−, N−, β-COO−) coordination modes including the N-termini, while the histidine sites are available for the formation of the (Nim, N−, N−) binding mode resulting in the preference of dinuclear complex formation

Cu(II) and Ni(II) Interactions with the Terminally Blocked Hexapeptide Ac-Leu-Ala-His-Tyr-Asn-Lys-amide Model of Histone H2B (80–85)

The N- and C-terminal blocked hexapeptide Ac-Leu-Ala-His-Tyr-Asn-Lys-amide (LAHYNK) representing the 80–85 fragment of histone H2B was synthesized and its interactions with Cu(II) and Ni(II) ions were studied by potentiometric, UV-Vis, CD, EPR, and NMR spectroscopic techniques in solution. Our data reveal that the imidazole N(3) nitrogen atom is the primary ligating group for both metal ions. Sequential amide groups deprotonation and subsequent coordination to metal ions indicated an {Nimidazole, 3Namide} coordination mode above pH∼9, in all cases. In the case of Cu(II)-peptide system, the almost exclusive formation of the predominant species CuL in neutral media accounting for almost 98% of the total metal ion concentration at pH 7.3 strongly indicates that at physiological pH values the sequence -LAHYNK- of histone H2B provides very efficient binding sites for metal ions. The imidazole pyrrole N(1) ionization (but not coordination) was also detected in species CuH−4L present in solution above pH ∼ 11