Anti-proliferative and antitumor activity of organotin(IV) compounds. An overview of the last decade and future perspectives.

Organotins(IV) exhibit significant in vitro anti-proliferative activity, while the in vivo tests are encouraging. The recent reports on the anti-proliferative activity of organotin(IV) compounds are summarized in this review. The period covered by this work goes back to 2009 until late 2018, while the earlier ones, are included over the previous review of our group published by S.

Recent advances on antimony(III/V) compounds with potential activity against tumor cells.

Antimony one of the heavier pnictogens, has been in medical use against microbes and parasites as well. Antimony-based drugs have been prescribed against leishmaniasis since the parasitic transmission of the tropical disease was understood in the beginning of the 20th century. The activity of arsenic against visceral leishmaniasis led to the synthesis of an array of arsenic-containing parasitic agents, among them the less toxic pentavalent antimonials: Stibosan, Neostibosan, and Ureastibamine.

Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and its complexes.

Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride [(tert-Bu-)(2)(HO-Ph)](2)SnCl(2) (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)(2)(HO-Ph)](2)Sn(PMT)(2)} (2), {[(tert-Bu-)(2)(HO-Ph)](2)Sn(MPMT)(2)} (3), {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(PYT)} (4) and {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, (1)H-, (13)C-, (119)Sn-NMR, EPR, FT-IR, Raman and Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1–5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1–5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2.

DNA strand breakage induced by CuII and NiII, in the presence of peptide models of histone H2B.

In the present study we used the plasmid relaxation assay, a very sensitive method for detection of DNA strand breaks in vitro, in order to evaluate the role of peptide fragments of histone H2B in DNA strand breakage induced by copper and nickel. We have found that in the presence of peptides modeling the histone fold domain (H2B(32-62) and H2B(63-93)) as well as the N-terminal tail (H2B(1-31)) of histone H2B there is an increased DNA damage by Cu(2+)/H(2)O(2) and Ni(2+)/H(2)O(2) reaction mixtures. On the contrary, the C-terminal tail (H2B(94-125)) seems to have a protective role on the attack of ROS species to DNA.

Copper effective binding with 32-62 and 94-125 peptide fragments of histone H2B.

In an attempt to investigate the role of histone H2B in Cu(II) induced toxicity and carcinogenesis, we synthesized the terminally blocked peptides H2B(32-62) (SRKESYSVYVYKVLKQVH(48)PDTGISSKAMGIM) and Η2Β(94-125) (IQTAVRLLLPGELAKH(110)AVSEGTKAVTKYTSS), mimicking the N-terminal histone-fold domain and C-terminal tail of histone H2B, respectively and studied their interaction with Cu(II) ions by means of potentiometric titrations and spectroscopic techniques (UV-visible, CD and EPR). Both peptides, H2B(32-62) and H2B(94-125), interacted efficiently with Cu(II) ions, forming several species from pH 4 to 11, with His(48) and His(110) serving as anchors for metal binding. In H2B(32-62), the effective Cu(II) binding is emphasized by the formation of a soluble Cu(II)-H2B(32-62) complex, unlike the unbound peptide that precipitated over pH 7.

The possible role of 94-125 peptide fragment of histone H2B in nickel-induced carcinogenesis.

The molecular mechanism by which nickel carcinogenicity is exerted is not fully understood. However, it is believed to involve DNA damage and epigenetic effects in chromatin, resulting from metal binding to the cell nucleus. Histone nuclear proteins are the major candidates for metal binding not only due to their abundance but also due to the presence of strong binding sites within their sequence.

Coordination of Cu(2+)and Ni(2+) with the histone model peptide of H2B N-terminal tail (1-31 residues): A spectroscopic study.

The interaction of Cu(2+) and Ni(2+) with the N-terminal tail of histone H2B, the 31 amino acid peptide H2B(1-31) (Ac-PEPAKSAPAPKKG(13)SKKAVTKAQKKD(25)GKKRKR-NH(2)), studied by various spectroscopic techniques (UV/Vis, CD, EPR and NMR) are described. The results showed the formation of Cu(2+)-H2B(1-31) complexes above pH 7.3 most probably through the beta-carboxylate group of D25.

Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides.

The reactions of tetrachloroauric(III) acid (HAuCl4) with the thioamides; 2-mercapto-benzothiazole (mbztH) and 5-ethoxy-2-mercapto-benzimidazole (EtmbzimH) lead to the desulfuration of the ligands and the formation of the ionic complexes {[AuCl4]- [bztH2]+} (1), and {[AuCl4]- [EtbzimH2]+ (H2O)} (2) (where bztH2+ and EtbzimH2+ are the desulfurated cations of the starting ligands). The reaction of HAuCl4 with 2-mercapto-nicotinic acid (mnaH2), however results in the formation of 2-sulfonate-nicotininc acid (C6H5NO5S) (3) with the simultaneous oxidation of the sulfur atom. On the other hand, the reactions of the gold(I) complex [Au(tpp)Cl] (4) (tpp = triphenylphosphine (Ph3P)) with the thioamides; 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) in the presence of potassium hydroxide resulted in the formation of the gold(I) complexes of formulae [Au(tpp)(mtzd)] (5), [Au(tpp)(mbzt)] (6) and [Au(tpp)(Clmbzt)] (7) without ligand desulfuration.

Structural motifs and biological studies of new antimony(III) iodide complexes with thiones.

Eight new antimony(III) iodide complexes of the heterocyclic thioamides, 2-mercapto-1-methylimidazole (MMI), 2-mercaptobenzimidazole (MBZIM), 5-ethoxy-2-mercaptobenzimidazole (EtMBZIM), 2-mercaptothiazolidine (MTZD), 3-methyl-2-mercaptobenzothiazole (NMeMBZT), 2-mercapto-3,4,5,6-tetrahydropyrimidine (tHPMT), 2-mercaptopyridine (PYT), and 2-mercaptopyrimidine (PMT) of formulas {[SbI(3)(MMI)(2)].MeOH} (1), [SbI(3)(MBZIM)(2)] (2), {[SbI(2)(mu(2)-I)(EtMBZIM)(2)](2).H(2)O} (3), [SbI(3)(MTZD)] (4), [(NMeMBZT)SbI(2)(mu(2)-I)(2)(mu(2)-S-NMeMBZT)SbI(2) (NMeMBZT)] (5), {[SbI(3)(tHPMT)(3)].

Synthesis, characterization, and biological studies of organotin(IV) derivatives with o- or p-hydroxybenzoic acids.

Organotin(IV) complexes with o- or p-hydroxybenzoic acids (o-H(2)BZA or p-H(2)BZA) of formulae [R(2)Sn(HL)(2)] (where H(2)L = o-H(2)BZA and R = Me- (1), n-Bu- (2)); [R(3)Sn(HL)] (where H(2)L = o-H(2)BZA and R = n-Bu- (3), Ph- (4) or H(2)L = p-H(2)BZA and R = n-Bu- (5), Ph- (6)) were synthesized by reacting a methanolic solution of di- and triorganotin(IV) compounds with an aqueous solution of the ligand (o-H(2)BZA or p-H(2)BZA) containing equimolar amounts of potassium hydroxide. The complexes were characterized by elemental analysis, FT-IR, Far-IR, TGA-DTA, FT-Raman, Mössbauer spectroscopy, (1)H, (119)Sn-NMR, UV/Vis spectroscopy, and Mass spectroscopy. The X-ray crystal structures of complexes 1 and 2 have also been determined.

Interaction of histone H2B (fragment 63-93) with Ni(ii). An NMR study.

The behaviour of the 31 mer peptide (Ac-NSFVNDIFERIAG(13)EASRL(18)A(19)H(20)YNKRS(25)TITSRE-NH(2)), modelling the histone-fold domain (63 to 93 residues) of H2B, towards Ni(ii) was investigated by multidimensional NMR spectroscopy (1D, 2D TOCSY, NOESY and (13)C-HSQC). The coordination involved the imidazole of His20 and three amide nitrogens of His20, Ala19 and Leu18, similar to the one shown by the hexapeptide LAHYNK contained in the 31 mer peptide. The solution structure of the Ni(ii) complex with the tridecapeptide comprising histone's H2B 75-87 residues, was elucidated from the NOE cross correlations observed in the 2D-NOESY spectrum.

New antimony(III) bromide complexes with thioamides: synthesis, characterization, and cytostatic properties.

New antimony(III) bromide complexes with the heterocyclic thioamides, thiourea (TU), 2-mercapto-1-methylimidazole (MMI), 2-mercapto-benzimidazole (MBZIM), 2-mercapto-5-methyl-benzimidazole (MMBZIM), 5-ethoxy-2-mercapto-benzimidazole (EtMBZIM), 2-mercapto-3,4,5,6-tetrahydro-pyrimidine (tHPMT), 2-mercaptopyridine (PYT), 2-mercapto-thiazolidine (MTZD), 3-methyl-2-mercaptobenzothiazole (MMBZT), and 2-mercaptopyrimidine (PMTH) of formulas [SbBr(3)(TU)(2)] (1), [SbBr(3)(MMI)(2)] (2), {[SbBr(2)(MBZIM)(4)](+) [Br](-) H(2)O} (3), {[SbBr(2)(mu(2)-Br)(MMBZIM)(2)](2)} (4), {[SbBr(2)(mu(2)-Br)(EtMBZIM)(2)](2) MeOH} (5), {[SbBr(3)(mu(2)-S-tHPMT)(tHPMT)](n)} (6), {[SbBr(2)(mu(2)-Br)(PYT)(2))(n)} (7), {[SbBr(2)(mu(2)-Br)(MTZD)(2)](n)} (8), [SbBr(3)(MMBZT)(2)] (9), and {[SbBr(5)](2-)[(PMTH(2)(+))(2)]} (10) have been synthesized and characterized by elemental analysis, conductivity measurements, FTIR spectroscopy, FT-Raman spectroscopy, TG-DTA analysis, and X-ray powder diffraction. The crystal structures of 3, 4, 5, 6, 7, 8, and 10 were also determined by X-ray diffraction. In 3, four sulfur atoms from thione ligands and two bromide ions form an octahedral (O(h)) cationic [SbS(4)Br(2)](+) species in which the two bromide anions lie at axial positions.

Interaction of Cu(II) and Ni(II) with the 63-93 fragment of histone H2B.

Chromatin proteins are believed to represent reactive sites for metal ion binding. We have synthesized the 31 amino acid peptide Ac-NSFVNDIFERIAGEASRLAHYNKRSTITSRE-NH2, corresponding to the 63-93 fragment of the histone H2B and studied its interaction with Cu(II) and Ni(II). Potentiometric and spectroscopic studies (UV-vis, CD, NMR and EPR) showed that histidine 21 acts as an anchoring binding site for the metal ion.

Structural motifs of diiodine complexes with amides and thioamides.

The reaction of 2-pyrimidone hydrochloride ([C(4)H(5)N(2)O](+)[Cl](-) or [PMOH(2)](+)[Cl](-)) with diiodine in a dichloromethane-methanol solution resulted in the formation of ([C(4)H(5)N(2)O](+))(2)[I(2)Cl(2)](2-) (1) complex. The compound was characterized by elemental analysis, FT-IR, DTA-TG and conductivity titrations. The crystal structure of 1 was also determined by X-ray diffraction at 294(1) K.

Complex formation processes of terminally protected peptides containing two or three histidyl residues. Characterization of the mixed metal complexes of peptides.

Copper(II), nickel(II) and zinc(II) complexes of the peptides Ac-HVVH-NH2 and Ac-HAAHVVH-NH2 have been studied by potentiometric, UV-vis, CD, EPR and NMR spectroscopic measurements. Both tetra and heptapeptides can form relatively stable macrochelates with copper(II), nickel(II) and zinc(II) ions, in which the ligands are coordinated via the side-chain imidazole functions. Formation of the macrochelates slightly suppresses, but cannot prevent the copper(II) and nickel(II) ion promoted deprotonation and coordination of the amide functionalities.

Synthesis, Characterization and Antiviral Properties of Pd(II) Complexes With Penciclovir.

With the aim to improve and extend the antiviral activity of the antiherpic drug penciclovir, to a wider spectrum of viruses, we have synthesized and characterized new binary and ternary complexes of Pd(II) of formulae cis-(pen)(2)PdCl(2) and cis,[(nucl)(2)Pd(pen)(2)]Cl(2), where nucl = guanosine, inosine, cytidine or penciclovir. The characterization was mainly based on IR and (1)H NMR spectroscopy, and the results showed that in all prepared complexes, penciclovir coordinates to the metal through N7. The far-i.

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 {N(imidazole), 3N(amide)} coordination mode above pH approximately 9, in all cases.

Crystal structure and antitumor activity of the novel zwitterionic complex of tri-n-butyltin(IV) with 2-thiobarbituric acid.

A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)(3)Sn(TBA) H(2)O] (1) has been synthesized and characterized by elemental analysis and (119)Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal.

1H NMR study of the enantioselective binding of lambda- and delta-[Ru(bpy)2(m-bpy-GHK)]Cl2 to the deoxynucleotide duplex d(5'-C1G2C3G4A5A6T7T8C9G10C11G12-3')2.

The interaction of the diastereomeric complexes Lambda- and Delta - [Ru(bpy)(2)(m - GHK)]Cl(2), (GHK = glycine-histidine-lysine) to the deoxynucleotide duplex d(5'-CGCGAATTCGCG-3')(2) was studied by means of (1)H NMR spectroscopy. The diastereomers interact with the oligonucleotide duplex differently. The Delta - [Ru(bpy)(2) (m - GHK)]Cl(2) is characterized by major groove binding close to the central part of the oligonucleotide, with both the peptide and the bipyridine ligand of the complex involved in the binding.

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.

Communication: synthesis of a novel triphenyltin(IV) derivative of 2- mercaptonicotinic acid with potent cytotoxicity in vitro.

A novel triphenyltin(IV) derivative of 2-mercaptonicotinic acid (H(2)mna) of formula {[(C(6)H(5))(3)Sn](2)(mna).[(CH(3))(2)CO]} (1) has been synthesized and characterized by elemental analysis and (1)H, (13)C-NMR, and FT-IR spectroscopic techniques. The crystal structure of complex (1) has been determined by single crystal X-ray diffraction analysis at 173(1) K.

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).

Coordination properties of Cu(II) and Ni(II) ions towards the C-terminal peptide fragment -TYTEHA- of histone H4.

In order to reveal more information about the toxicity caused by metals and furthermore their influence to the physiological metabolism of the cell, the hexapeptide model Ac-ThrTyrThrGluHisAla-am representing the C-terminal 71-76 fragment of histone H4 which lies into the nucleosome core, was synthesized. A combined pH-metric and spectroscopic UV-VIS, EPR, CD and NMR study of Ni(II) and Cu(II) binding to the blocked hexapeptide, revealed the formation of octahedral complexes involving imidazole nitrogen of histidine, at pH 5 and pH 7 for Cu(II) and Ni(II) ions respectively. In basic solutions a major square-planar 4 N Ni(II)-complex, adopting a {N(Im), 3N(-)} coordination mode, was formed.

Synthesis, structural characterization and biological study of new organotin(IV), silver(I) and antimony(III) complexes with thioamides.

An overview of our work on the synthesis and biological activity of a series of tin(IV), silver(I) and antimony(III) complexes with thioamides is reported. Organotin(IV) complexes of formulae (n-Bu)2Sn(MBZT)2 (1), Me2Sn(CMBZT)(2) (2), {(Ph3Sn)2(MNA) (Me2CO)} (3), Ph3Sn(MBZT) (4), Ph3Sn(MBZO) (5), Ph3Sn(CMBZT) (6), Ph2Sn(CMBZT)2 (7) and (n-Bu)2Sn(CMBZT)2 (8), Me2Sn(PMT)2 (9), (n-Bu)2Sn(PMT)2 (10), Ph2Sn(PMT)2 (11), Ph3Sn(PMT) (12) {where MBZT=2-mercapto-benzothiazole, CMBZT=5-chloro-2-mercapto-benzothiazole, H2MNA=2-mercapto-nicotinic acid, MBZO=2-mercapto-benzoxazole and PMTH=2-mercapto-pyrimidine} were characterized by spectroscopic (NMR, IR, Mossbauer, etc.) and X-ray diffraction techniques and their influence on the peroxidation of oleic acid was studied.

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-NH(2) and Ac-HVGDH-NH(2)) 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.