Non-covalent interactions in organotin(IV) derivatives of 5,7-ditertbutyl- and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine as recognition motifs in crystalline self- assembly and their in vitro antistaphylococcal activity

Non-covalent interactions are known to play a key role in biological compounds due to their stabilization of the tertiary and quaternary structure of proteins [1]. Ligands similar to purine rings, such as triazolo pyrimidine ones, are very versatile in their interactions with metals and can act as model systems for natural bio-inorganic compounds [2]. A considerable series (twelve novel compounds are reported) of 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) and 5,7-diphenyl- 1,2,4-triazolo[1,5-a]pyrimidine (dptp) were synthesized and investigated by FT-IR and 119Sn M\uf6ssbauer in the solid state and by 1H and 13C NMR spectroscopy, in solution [3]. The X-ray crystal and molecular structures of Et2SnCl2(dbtp)2 and Ph2SnCl2(EtOH)2(dptp)2 were described, in this latter pyrimidine molecules are not directly bound to the metal center but strictly H-bonded, through N(3), to the -OH group of the ethanol moieties. The network of hydrogen bonding and aromatic interactions involving pyrimidine and phenyl rings in both complexes drives their self-assembly. Noncovalent interactions involving aromatic rings are key processes in both chemical and biological recognition, contributing to overall complex stability and forming recognition motifs. It is noteworthy that in Ph2SnCl2(EtOH)2(dptp)2 \u3c0\u2013\u3c0 stacking interactions between pairs of antiparallel triazolopyrimidine rings mimick basepair interactions physiologically occurring in DNA (Fig.1). M\uf6ssbauer spectra suggest for Et2SnCl2(dbtp)2 a distorted octahedral structure, with C-Sn-C bond angles lower than 180\ub0. The estimated angle for Et2SnCl2(dbtp)2 is virtually identical to that determined by X-ray diffraction. Ph2SnCl2(EtOH)2(dptp)2 is characterized by an essentially linear C-Sn-C fragment according to the X-ray all-trans structure. The compounds were screened for their in vitro antibacterial activity on a group of reference staphylococcal strains susceptible or resistant to methicillin and against two reference Gramnegative pathogens [4] . We tested the biological activity of all the specimen against a group of staphylococcal reference strains (S. aureus ATCC 25923, S. aureus ATCC 29213, methicillin resistant S. aureus 43866 and S. epidermidis RP62A) along with Gram-negative pathogens (P. aeruginosa ATCC9027 and E. coli ATCC25922). Ph2SnCl2(EtOH)2(dptp)2 showed good antibacterial activity with a MIC value of 5 \u3bcg mL-1 against S. aureus ATCC29213 and also resulted active against methicillin resistant S. epidermidis RP62A

Di-μ-azido-κ4 N:N-bis­{aqua­[bis­(1H-benzimidazol-2-ylmeth­yl)amine]­copper(II)} dinitrate

In the centrosymmetric dinuclear title complex, [Cu2(N3)2(C16H15N5)2(H2O)2](NO3)2, the CuII ion is in a distorted octa­hedral coordination environment with long axial Cu—Nazide [2.821 (6) Å] and Cu—Owater [2.747 (5) Å] bonds as a result of the Jahn–Teller effect. Two symmetry-related azide ligands bridge in μ2-modes giving a Cu⋯Cu distance of 3.533 (2) Å. In the crystal, N—H⋯O and O—H⋯O hydrogen bonds link the components into a three-dimensional network. In addition, there are weak inter­molecular C—H⋯N hydrogen bonds and π–π stacking inter­actions with centroid–centroid distances ranging from 3.562 (2) to 3.974 (2) Å

Organotin(IV) derivatives with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine and their cytotoxic activities: the importance of being conformers.

The organotin(IV) compounds Me2SnCl2(dbtp)(1), Me2SnCl2(dbtp)2 (2), Et2SnCl2(dbtp) (3), Et2SnCl2(dbtp)2 (4), Et2SnCl2(dptp) (5), nBu2SnCl2(dbtp)2 (6), nBu2SnCl2(dptp) (7), Ph2SnCl2(dbtp) (8), Ph2SnCl2(dptp)2 (9), where dbtp = 5,7-di-tert-butyl-1,2,4-triazolo[1,5-a]pyrimidine and dptp = 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine, have been tested towards their cytotoxic activity by MTT test on three tumor cell lines, HepG2 (human hepatocellular carcinoma), HeLa (human cervix adenocarcinoma) and MCF-7 (human breast cancer). Except for 1 and 2, which were ineffective, all compounds significantly showed a dose-dependent anti-proliferative effect toward the three cell lines. By calculated IC50 values, cytotoxicity of the complexes followed the order nBu > Ph > Et > Me for all the selected tumor cells. Organotin(IV) compounds (6-9)-induced cell death of HepG2 was considered to be apoptotic by measuring the exposure of phosphadytilserine to the outer membrane and observing the typical apoptotic morphological change by acridine orange/ethidium bromide staining. Flow cytometric analysis of propidium iodide-stained cells also demonstrated that organotin(IV) complexes caused apoptosis of HepG2 cells through cell arrest at G0-G1 phase. The crystal structure of 7 was investigated by X-ray diffraction analysis, exhibiting a distorted trigonal bipyramidal geometry with N, Cl as axial atoms and Cl and butyl groups in the equatorial plane. The triazolopyrimidine unit coordinates to the Sn atom through N(3) in a monodentate mode. Two conformational isomers (molecule A and B in the crystallographic independent unit) are cocrystallized in the solid state, a phenomenon that has been observed only occasionally. Conformational mobility of the cytotoxic complex 7 can sum up to the ligands ability to form Hbonds and π···π stacking, facilitating its intracellular uptake

New organotin(IV) complexes with L-Arginine,Nα-t-Boc-L-Arginine and L-Alanyl-L-Arginine.Synthesis, structural investigations and cytotoxic activity

Novel diorganotin(IV) derivatives of L-Arginine (HArg), Nα-(tert-Butoxycarbonyl)-L-Arginine (Boc-Arg-OH) and L-Ala-L-Arg (H2Ala-Arg), H2NC(=NH)NH(CH2)3CH(NHR)CO2H, where R = H in HArg, R = C(O)OC(CH3)3 in Boc-Arg-OH, R = H2NCH(CH3)CO in H2Ala-Arg and triorganotin(IV) derivatives of Boc-Arg-OH have been synthesized and structurally characterized. The complexes were investigated by FT-IR and 119Sn Mössbauer in the solid state and by 1H, 13C, 119Sn and 1H-1H COSY NMR spectroscopy, in solution. The spectroscopic characterization leading to the proposed molecular structures was accomplished on the basis of these experiments. L-Arginine appears to behave as a chelating ligand through carboxylate and -NH2 groups in Me2Sn(Arg)2, while in N-t-Boc-L-Arginine complex, the N-protected amino group being exempted from coordination, only the carboxylate groups are effectors of bonding to the organometallic moieties. FT-IR spectra give a clear indication that guanidino groups in all the complexes are not involved in coordination, since (C=N-H) frequency of the terminal guanidino group is fairly constant and unshifted relative to the free ligand. The biological activity of organotin(IV)-complexes was also investigated by use of human HT29 colorectal carcinoma cells. The cytotoxic activity of the compounds was determined by the MTT quantitative colorimetric assay, capable of detecting viable cells in comparison with that exerted by cisplatin. A marked cytotoxic activity for nearly all complexes, is evident being higher than that exerted by cisplatin, while no significant improvement of activity was observed for Me2Sn(Arg)2 and Me2Sn(Ala-Arg), which was confirmed by IC50 values. Then, we assessed whether the cytotoxicity induced by organotin(IV) complexes was associated with the induction of apoptosis. Light microscopy analysis, performed to study the morphological changes induced in HT29 cells, confirmed the results obtained with MTT test. No significant morphological alterations were observed in HT29 cells after treatment with Me2Sn(Ala-Arg) and Me2Sn(L-Arg)2. Cells treated with nBu2Sn(Boc-Arg)2, nBu2Sn(Ala-Arg), nBu3Sn(Boc-Arg) and Me3Sn(Boc-Arg), appeared rounded, isolated and detached from culture substrate, indicating the commitment to apoptotic cell death

Synthesis, characterization, and in vitro antimicrobial activity of organotin(IV) complexes with triazolo-pyrimidine ligands containing exocyclic oxygen atoms.

Tri-organotin(IV) complexes of the triazolo-pyrimidine derivatives 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5a]pyrimidine (5HtpO), 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5a]pyrimidine (HmtpO), and 4,5,6,7-tetrahydro-5,7-dioxo-[1,2,4]triazolo-[1,5a]pyrimidine (H2tpO2), and the diorganotin derivative n-Bu2Sn(tpO2), were synthesized and characterized by means of infrared and 119Sn Mo¨ssbauer spectroscopy. In all the complexes obtained the triazolopyrimidines act as multidentate ligands producing polymeric structures. A trigonal bipyramidal arrangement of the ligands around the tin atom is proposed for triorganotin(IV) derivatives, with organic groups on the equatorial plane and bridging anionic ligands. DFT calculations were performed on the structure of H2tpO2 and on its mono- an di-anions, to investigate their harmonic vibrational modes. The observed trend of the experimental and calculated carbonyl stretching frequencies furnishes a support for the interpretation of the structure of the organotin(IV) complexes obtained with this ligand. The structure of n-Bu2Sn(tpO2) was elucidated by quantum chemical calculations, performed on a model system of the polymeric complex by a two layers ONIOM method. The combined experimental and theoretical results obtained support for a trans-n-Bu2 distorted octahedral geometry, with the tpO2 2 units acting as bis-chelate ligands bridging the diorganotin(IV) moieties, and with the N(1)O(7) and N(4)O(5) chelating groups in the equatorial plane showing a cis-O2, or cis-N2, coordination. In vitro antimicrobial tests were performed on n-Bu3Sn(HtpO2) and Ph3Sn(HtpO2), and a good antifungal and antibiofilm activity was observed, in particular for n-Bu3Sn(HtpO2)

Synthesis of platinum complexes with 2-(5-perfluoroalkyl-1,2,4-oxadiazol-3yl)-pyridine and 2-(3-perfluoroalkyl-1-methyl-1,2,4-triazole-5yl)-pyridine ligands and their in vitro antitumor activity

Five new mononuclear Pt(II) complexes with 5-perfluoroalkyl-1,2,4-oxadiazolyl-pyridine and 3-perfluoroalkyl-1,2,4-triazolyl-pyridine ligands are reported. The ligands 2-(5-perfluoroheptyl-1,2,4-oxadiazole-3yl)-pyridine (pfhop), 2-(5-perfluoropropyl)-1,2,4-oxadiazole-3yl)-pyridine (pfpop), 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and their complexes [PtCl2(pfhop)(2)]center dot 1.5 DMSO (2a), [PtCl2(pfpop)(2)]center dot 1.5 DMSO (3a), [PtCl2(pfhtp)(2)]center dot 1.5 DMSO (4a), PtCl2(pfhtp) (4b), [PtCl2(PfPtP)(2)]center dot 1.5 DMSO (5a) have been synthesized and structurally characterized. The complexes 2a, 3a, 4a and 5a have the same chemical environment of Pt(II) where PtCl2 moieties coordinate two molecules of ligand via N1 atom of pyridine in the case of pfhop and pfpop, and N2 atom of 1,2,4-triazole in the case of pfhtp and pfptp. For 4b, pfhtp behaves as bidentate ligand, coordinating Pt(II) ion via N4 atom of triazole and N1 atom of pyridine. All complexes have been tested in vitro by 3-(4,5-dimethyl-2-thiazolyl)bromide-2,5-diphenyl-2 H-tetrazolium (MTT) test on four tumor cell lines MCF-7 (human breast cancer), HepG2 (human hepatocellular carcinoma), HCT116 (human colorectal carcinoma). Compounds 2a and 4b showed a dose-dependent anti-proliferative effect against the three tumor cell lines whereas did not affect viability of intestinal normal-like differentiated Caco-2 cells. The cell death of HepG2, MCF-7 and HCT116 induced by the compounds, was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and observing the typical apoptotic morphological change by acridine orange (AO)/ethidium bromide (EB) stainin

Synthesis, spectroscopic characterization and in vitro antimicrobial activity of diorganotin(IV) dichloride adducts with [1,2,4]triazolo-[1,5-a]pyrimidine and 5,7-dimethyl-[1,2,4]triazolo-[1,5,a]pyrimidine.

The heterocyclic ligands [1,2,4]triazolo-[1,5-a]pyrimidine (tp) and 5,7-dimethyl-[1,2,4]triazolo-[1,5-a]pyrimidine (dmtp), react with diorganotin dichlorides giving the addition compounds Me2SnCl2(tp)2, Et2 SnCl2(tp)2, Me2 SnCl2(dmtp)2, Et2 SnCl2(dmtp)2, Bu2SnCl2(dmtp), Ph2SnCl2(dmtp). The organotin:ligand stoichiometry goes from 1:2 to 1:1 by increasing the steric hindrance of the organic groups bound to tin. The compounds have been characterized by means of infrared, 119Sn Mo¨ssbauer and 1H AND 13C NMR spectroscopy. The ligands presumably coordinate to tin classically through the nitrogen atom at the position 3. The 1:1 complexes adopt trigonal bipyramidal structures, with the organic groups on the equatorial plane and the ligand in the apical position. All-trans octahedral structures are inferred for the 1:2 complexes, except for Et2SnCl2(tp)2, characterized by a skew-trapezoidal structure. 119Sn Mo¨ssbauer measurements, at room temperature, in concomitance with DFT calculations, performed on isomeric structures of R2SnCl2(tp)2 (R = Me, Et), allowed us to conclude that the all-trans octahedral coordination induces self-assembly in the solid state, possibly accomplished through p–p stacking interactions among the planar ligands coordinated to the organotin(IV) compound, while the skew-trapezoidal structure attributed to Et2SnCl2(tp)2, induces the formation of monomeric adducts in the solid state. In vitro antimicrobial tests showed that [n-Bu2SnCl2(dmtp)] has interesting properties as anti Gram-positive and antibiofilm agent

Triorganotin(IV) derivatives of 7-amino-2-(methylthio)[1,2,4]triazolo [1,5-a]pyrimidine-6-carboxylic acid. Synthesis, spectroscopic characterization, in vitro antimicrobial activity and X-ray crystallography

Triorganotin(IV) complexes of the 7-amino-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (HL), Me3SnL(H2O), (1), [n-Bu3SnL]2(H2O), (2), Ph3SnL(MeOH), (3), were synthesized by reacting the amino acid with organotin(IV) hydroxides or oxides in refluxing methanol. The complexes have been characterized by elemental analysis, 1H, 13C and 119Sn NMR, IR, Raman and 119Sn Mössbauer spectroscopic techniques. Single crystal X-ray diffraction data were obtained for compounds (2) and (3). Ph3SnL(MeOH) presents a trigonal bipyramidal structure with the organic groups on the equatorial plane and the axial positions occupied by a ligand molecule, coordinated to tin through the carboxylate, and a solvent molecule, MeOH. A similar structure is proposed for Me3SnL(H2O) on the basis of analytical and spectroscopic data. The tributyltin(IV) derivative, [n-Bu3SnL]2(H2O), is characterized by two different tin sites with similar tbp geometry featured by butyl groups on the equatorial plane. Sn(1) and Sn(2) atoms are axially bridged by a ligand molecule binding through the N(4) and the carboxylate group; the two coordination spheres are saturated by another ligand molecule, binding the metal through the carboxylate group, and a water molecule, respectively. Antimicrobial tests on compounds 1 and 2 showed in vitro activity against Gram-positive bacteria

Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands

Three novel cisplatin analogues were synthesized, designed according to an approach which violates the ‘‘classical’’ structure–activity relationship, by replacing the diamine ligands with a planar N donor heterocycle giving a sterically hindered complex. Moreover, the sterical hindrance of antitumor drug candidates potentially makes them less susceptible to deactivation by sulphur-containing proteins and helping to overcome resistance mechanisms. The resulting mononuclear complexes of sterically hindered polidentate heterocyclic N ligands [PtCl(bbp)]Cl (1) [bbp = 2,6-bis(2-benzimidazolyl)pyridine], [PtCl2(dptdn)](H2O) (2) [dptdn = sodium 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine-400,400 0-disulfonate] and [(dptdn)(dpt)Pt]Cl2(H2O) (3) [dpt = 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine] have been prepared and structurally characterised. Both neutral and ionic complexes are present, with monofunctional (1) and bifunctional Pt(II) moieties (2) and coordinatively saturated Pt(II) ions in the mixed ligand complex (3), whose size and shape enable them to behave as novel scaffolds for DNA binding. All complexes were tested ‘‘in vitro’’ for their biological activity on human HT29 colorectal carcinoma and HepG2 hepatoma cells. The complexes (1) and (3), endowed with a positive charge, showed a potent cytotoxic activity and reduced cell viability with an efficacy higher than that of cisplatin; whilst the neutral bifunctional compound (2) was inactive. IC50 values have been calculated for the active compounds. The cytotoxic effects were confirmed by the accumulation of treated cells in subG0/G1 phase of cell cycle, by the loss of mitochondrial potential (Dwm) and by the chromatin condensation or fragmentation observed by means of fluorescence microscopy after Hoechst 33258 nuclear staining. A study on intracellular platinum uptake in HT29 cell line has been also performed and data obtained strongly suggest that the cytotoxicity of new tested complexes reported in this work is based on a different pharmacodynamic pattern with respect to cisplatin

Pt(II) complex @mesoporous silica: preparation, characterization and study of release

Cisplatin analogs, having cytotoxic activity higher than that exerted by cisplatin, have recently triggered considerable interest by the community. The cis-[PtCl2(DMSO)HL]·2DMSO, where HL = 7-amino-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid, has shown a potent cytotoxic activity on HepG2 hepatocarcinoma cells, while under identical conditions, it did not affect normal immortalized human liver cells (Chang). In this work, the above complex has been incorporated into MCM41 mesoporous silica, pure and functionalized with amino group, which is considered one of the best host for a drug delivery system for carrying high dosages of a variety of drugs in their mesopores. Since the controlled release of an anticancer drug helps to maintain its therapeutic level for an extended time period while minimizing undesirable high peaks immediately following administration, the in vitro tests have been performed in order to obtain the corresponding drug release profile. The investigated system demonstrated to be an efficient system for pharmaceutic controlled release. A deepened characterization of the systems has been performed in order to known their structure and features and to speculate the mechanisms involved in the release