Synthesis and spectroscopic studies of platinum(II) complexes of N,N′-dicyclohexylethylenediamine

The platinum(II) complexes of the formula [Pt(DCHEDA)X₂], where DCHEDA is N,N′-dicyclohexylethylenediamine and X⁻ is CL⁻, Br⁻, I⁻, 0.5C₂O₄²⁻ (oxalate), 0.5C₃H₂O₄²⁻ (malonate), 0.5C₉H₄O₆²⁻ (4-carboxyphthalate), 0.5S₂O₃²⁻ or 0.5SO₄²⁻, have been synthesized and characterized by UVVis, IR, and ¹H NMR spectral techniques. All the above complexes are non-electrolytes in DMF/H₂O, except the sulphate complex which becomes a 1:1 electrolyte after incubation for 24 h at 28 °C. The halide complexes were also studied by X-ray photoelectron spectroscopy and these data suggest that there is π-bonding from platinum to halide in these complexes. The oxalate, malonate and sulphate bind in their complexes as bidentate ligands to platinum through two oxygen atoms whereas the thiosulphate in its complex binds as a bidentate ligand to platinum through one oxygen atom and one sulphur atom.     

Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

The polymeric [PdCl(dithiocarbamate)]_n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH₂)₄NCS₂⁻) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO₂CCH₂N(CH₃)CS₂⁻), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarbamate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)]_nCl_n (diamine = dab or dah) were obtained, in which each Pd(dithiocarbamate)⁺ unit binds to the NH₂ group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd₂Cl₂(dithiocarbamate)₂(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocarbamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.     

Synthesis,DNA/BSA binding studies and in vitro biological assay of nickel(II) complexes incorporating tridentate aroylhydrazone and triphenylphosphine ligands

Abstract

Two new nickel (II) triphenylphosphine complexes derived from tridentate aroylhydrazone ligands [H₂L¹ = 2-hydroxy-3-methoxybenzylidene)benzohydrazone and H₂L² = N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone] and triphenylphosphine were prepared and their molecular structures were determined by single crystal X-ray diffraction analysis. Both nickel(II) complexes showed slightly distorted square planar geometry with one tridentate aroylhydrazone ligand coordinated through ONO donor atoms and one triphenylphosphine ligand coordinated to the nickel center through the phosphorus atom. DNA interaction studies indicated that both complexes possessed higher affinity to herring sperm DNA (HS-DNA) than the corresponding free aroylhydrazone ligand. Molecular docking investigations showed that both complexes could bind to DNA through intercalation of the phenyl rings between adjacent base pairs in the double helix. Meanwhile, bovine serum albumin (BSA) binding studies revealed the complexes could effectively interact with BSA and change the secondary structure of BSA. Further pharmacological evaluations of the synthesized complexes by in vitro antioxidant assays demonstrated high antioxidant activity against NO· and O₂˙^? radicals. The anticancer activity of each complex was assessed through in vitro cytotoxicity assays (CCK-8 kit) toward A549 and MCF-7 cancer cell and normal L-02 cell lines. Significantly, the Ni(II) complex derived from H₂L¹ ligand was found to be more effective cytotoxic toward MCF-7cancerous cell with the IC₅₀ value equaled 9.7?μM, which showed potent cytotoxic activity over standard drug cisplatin.

Abbreviations A549 human lung carcinoma cell

BSA bovine serum albumin

CCK-8 Cell Counting Kit-8

DFT density functional theory

DNA deoxyribonucleic acid

DPPH˙ 2,2-diphenyl-1-picrylhydrazyl

H₂L¹ 2-hydroxy-3-methoxybenzylidene)benzohydrazone N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone

H₂L² N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone

HOMO highest occupied molecular orbital

IC₅₀ the 50% activity

L-02 human normal liver cell

LOMO lowest unoccupied molecular orbital (LUMO)

MCF-7 human breast carcinoma cell

NO˙ nitric oxide

O₂˙^? superoxide anion

SOD superoxide dismutase

Communicated by Ramaswamy H. Sarma     

N⁶-Alkyladenosines: Synthesis and evaluation of in vitro anticancer activity

A series of adenosine analogues differently substituted in N⁶-position were synthesized to continue our studies on the relationships between structure and biological activity of iPA. The structures of the compounds were confirmed by standard studies of ¹H NMR, MS and elemental analysis. These molecules were then evaluated for their anti-proliferative activity on bladder cancer cells. We found that some of these compounds possess anti-proliferative activity but have no effect on cell invasion and metalloprotease activity.     

Synthesis, characterization, and reactivity of (π-allyl)palladium(II) wrap-around complexes with 1,3-dienes

Synthesis of a series of cationic “wrap-around” complexes, η³-, η²- (CH₂-CH-CHR-CH₂-CH₂-CHCHX) Pd(II)L⁺ (R = H, CH₃; X = H, Cl, CO₂Me; L = PPh₃, P(C₄H₄N)₃), is described. These chelate complexes were prepared by exposure of π-allyl chloride dimers, (η³-(CH₂-CX-CH₂)PdCl)₂, to either 1,3-butadiene or isoprene to yield π-allyl chloride dimers of the type (η³-CH₂CHCRCH₂CH₂CH = CH(X)PdCl)₂ which result from insertion of the diene into each π-allyl unit. Abstraction of chloride with either AgSbF₆ or NaB(Ar_F)₄ in the presence of L gives the cationic wrap-around complexes in high yields. Single crystal X-ray diffraction studies of 8a (R = -CH₃, X = -Cl, L = PPh₃) and 9a (R = -H, X = -Cl, L = PPh₃) show that Pd(II) adopts essentially a square planar geometry and the chelate arm occupies a syn orientation with respect to the allyl unit. Exposure of these wrap-around complexes to nitriles of differing basicities displaces the chelated alkene to varying extents and allows assessment of the relative strengths of chelation as a function of substituents, X and R. Initial rapid displacement of the chelated alkene yields a syn-π-allyl isomer which equilibrates with the anti-π-allyl isomer which cannot close to form a chelate. Treatment of 8b with 1,3-butadiene gives not polybutadiene but 2-chloro-4-methyl-1,E-4,6-heptatriene and 2-chloro-4-methyl-1,Z-4,6-heptatriene. Formation of these trienes is first-order in butadiene. This reaction serves as a model for chain-transfer in the polymerization of butadiene.     

Synthesis and antimicrobial activity of copper(II) and manganese(II) α,ω-dicarboxylate complexes

Copper(II) ,-dicarboxylate complexes of general formulae, [Cu(O₂C(CH₂)_nCO₂)]·xH₂O, [Cu(O₂C(CH₂)_nCO₂) (phen)₂]·xH₂O and [Cu(O₂C(CH₂)_nCO₂)(bipy)_y]·xH₂O (n=1–8; y=1, 2; phen = 1,10-phenanthroline; bipy = 2,2-bipyridine) were synthesised. These copper complexes, some related manganese(II) complexes and the metal-free ligands were screened in vitro for their ability to inhibit the growth of Candida albicans. Metal-free 1,10-phenanthroline and all of the copper(II) and manganese(II) phenanthroline complexes were potent growth inhibitors, with only one bipyridine complex, [Cu(O₂C(CH₂)CO₂)(bipy)₂]·2H₂O, having moderate activity. The remaining substances were effectively inactive. Complexes which were active against C. albicans also proved effective against C. glabrata, C. tropicalis and C. kreusi with the manganese complexes retaining superior activity. For the phenanthroline complexes the active drug species is thought to be the dication [M(phen)₂(H₂O)_n]²⁺ (M = Cu, Mn). Escherichia coli and Staphylococcus aureus were resistant to all of the metal complexes and also to metal-free 1,10-phenanthroline. Only the copper phenanthroline complexes showed intermediate activity against Pseudomonas aeruginosa.     

Synthesis,characterization and antitumour properties of some metal(II) complexes of 2-pyridinecarboxaldehyde 2′-pyridylhydrazone and related compounds

Metal complexes of 2-pyridinecarboxaldehyde 2′-pyridylhydrazone (PCPH) and related compounds with manganese(II), iron(II), cobalt(II), nickel(Il), copper(II), zinc(II) and platinum(II) were synthesized and characterized by magnetic susceptibility measurements down to liquid nitrogen temperature and also by electronic, infrared, electron spin resonance and Mössbauer spectra. All the metal(II) complexes appeared to be monomeric, high-spin, five-coordinate (square-pyramidal) (X = Cl⁻ or OAc⁻), except for Ni(PCPH)Cl₂ which is polymeric, high-spin, six-coordinate. Each ligand behaved as a tridentate NNN donor, via the pyridine nitrogen, azomethine nitrogen, and pyridine or quinoline nitrogen. One of the most active agents of this series, Cu(PCPH)Cl₂, showed antitumour activity against a variety of transplanted tumours, including Sarcoma 180, Ehrlich carcinoma and L1210 leukaemia sensitive to α(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of ³H-thymidine and ³H-uridine incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this agent.     

Synthesis,characterization, antimicrobial activity and structure–activity relationships of new aryldisulfonamides

A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33).     

Synthesis, crystal structures and spectroscopic properties of copper(I) complexes containing β-dialdiminato supporting ligands

Two mononuclear neutral copper(I) complexes, Cu(L¹)PPh₃ (1), Cu(L²)(PPh₃)₂ (2) ([L¹]⁻ = [{N(C₆H₃ⁱPr₂-2,6)C(H)}₂CPh]⁻; [L²]⁻ = [{N(C₆H₅)C(H)}₂CPh]⁻) have been synthesized and structurally characterized by X-ray crystallography. In complex 1, the copper(I) atom is in a distorted three-coordinate trigonal planar environment, whereas in complex 2 with the less sterically hindered β-dialdiminato ligand, the copper(I) atom is the centre of a four-coordinate distorted tetrahedron. At room temperature complexes 1 and 2 in a film of PMMA exhibit green emission at 543 and 549 nm with lifetimes of 5.28 and 5.32 ns, respectively.     

Synthesis and in vitro evaluation of α-synuclein ligands

Accumulation of misfolded α-synuclein in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD). To identify ligands having high binding potency toward aggregated α-synuclein, we synthesized a series of phenothiazine derivatives and assessed their binding affinity to recombinant α-synuclein fibrils using a fluorescent thioflavin T competition assay. Among 16 new analogues, the in vitro data suggest that compound 11b has high affinity to α-synuclein fibrils (K(i)=32.10 ± 1.25 nM) and compounds 11d, 16a and16b have moderate affinity to α-synuclein fibrils (K(i)≈50-100 nM). Further optimization of the structure of these analogues may yield compounds with high affinity and selectivity for aggregated α-synuclein.     

Extended structures sustained by hydrogen bonding and π-π interactions: Synthesis and characterization of Cd(II) complexes with bis(benzimidazolyl) ligands

Two new Cd(II) complexes, {[Cd(C4BIm)Cl₂] · DMF}_n (1) and [Cd(HC4BIm)Cl₃] · 3H₂O (2) (C4BIm = 1,4-bis(benzimidazolyl)butane and HC4BIm = mono-protonated 1,4-bis(benzimidazolyl)butane), have been prepared and characterized spectroscopically and crystallographically. In both complexes, the Cd(II) atom exhibits distorted tetrahedral coordination geometry with CdN₂Cl₂ and CdNCl₃ in 1 and 2, respectively. Complex 1 adopts a racemic structure built up from P- and M-helical [Cd(C4BIm)Cl₂]_n chains, which are alternately linked into two-dimensional network by N-H?Cl hydrogen bonds and further stabilized by the intermolecular π?π stacking. In complexes 2, the HC4BIm is monodentate, coordinating to Cd(II) ion via the unprotonated benzimidazolyl nitrogen donor to form mononuclear [Cd(HC4BIm)Cl₃]. The mononuclear units are linked by N-H?Cl hydrogen bonds to form one-dimensional planar belts, which interact via intermolecular π?π stacking to result in three-dimensional framework.     

Synthesis and anticancer activity of some 5-fluoro-2′-deoxyuridine phosphoramidates

Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-O-(t-butoxycarbonyl)-5-fluoro-2′-deoxyuridine (3′-BOC-FdU) (9a–9j) and 5-fluoro-2′-deoxyuridine (FdU) (10a–10j) were synthesized by means of phosphorylation of 3′-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a–9j were converted to the corresponding 10a–10j by removal of the 3′-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a–9j and 10a–10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a–10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.     

Synthesis and crystal structures of platinum (II) complexes with phosphine sulfide: cis-Dichloro[dimethylsulfoxide](triphenylphosphine sulfide) platinum (II) and (−)-cis-dichloro[(S)-methyl-p-tolylsulfoxide](triphenylphosphine sulfide) platinum (II)

The addition of triphenylphosphine sulfide (Ph₃PS) to bis-sulfoxide platinum (II) complexes [Pt(Me₂SO)₂Cl₂] and (−)-[Pt(Me-p-TolSO)₂Cl₂] yields mixed ligand complexes [Pt(Ph₃PS)(Me₂SO)Cl₂] (1) and (−)-[Pt(Ph₃PS)(Me-p-TolSO)Cl₂] (2), which are effective catalysts for hydrosilylation reaction. These mixed-ligand complexes were obtained in crystal state and analyzed by X-ray diffraction, ¹H, ³¹P and ¹⁹⁵Pt NMR; 2 was also studied by circular dichroism spectroscopy. Both complexes exist in CDCl₃ solution as a dynamic equilibrium of two geometric isomers with an approximate 1:10 ratio, but only cis-isomer is obtained on crystallization. The X-ray structures of the complexes have classical geometry, and phosphine sulfide and sulfoxides are coordinated via sulfur. The new structural data for simple platinum–Ph₃PS coordination bond, unaffected by chelation or bridging, were evaluated. The lengths of this bond are 2.300(4) Å in 1 and 2.305(3) Å in 2, respectively. PtSP angle equals 105.7(2)° in 1 and 104.05(13)° in 2, the PtSP plane is almost perpendicular to the coordination plane. The static trans-influence of Ph₃PS is estimated to be strong and close to that of S-coordinated Me₂SO. The complex 2 exhibits strong circular dichroism at a wavelength below 330 nm, caused both by inherent Me-p-TolSO stereogenic center and induced asymmetry of Ph₃PS.     

Tautomerization of 2-nitroso-N-arylanilines by coordination as N,N′-chelate ligands to rhenium(i) complexes and the anticancer activity of newly synthesized oximine rhenium(i) complexes against human melanoma and leukemia cells in vitro

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(i) complexes are described. The reaction of the halogenido complexes (CO)₅ReX (X=Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C₆H₃ClNO)NH(C₆H₄R)} (R = p-Cl, p-Me, o-Cl, H) (3a–d) in tetrahydrofurane (THF) yields the complexes fac-(CO)₃XRe{(C₆H₃ClNO)NH(C₆H₄R)} (6a–d, 7a–d) with the tautomerized ligand acting as a N,N′-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by ¹H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their ¹H and ¹³C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N′-chelating ligands for all Re(i) complexes. Biological activity of four oximine rhenium(i) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(i) complexes than leukemia cells. None of the ligands (3a–d) showed any significant anticancer activity.     

Exploiting azide–alkyne click chemistry in the synthesis,tracking and targeting of platinum anticancer complexes

Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop novel Pt-based anticancer drugs and to better understand the biological effects of Pt-based anticancer drugs at a cellular level. Innovative azide–alkyne cycloaddition–based approaches are being used to functionalise Pt-based complexes with biomolecules to enhance tumour targeting. Valuable information in relation to the mechanisms of action and resistance of Pt-based drugs is also being revealed through click-based detection, isolation and tracking of Pt drug surrogates in biological and cellular environments. Although less well-explored, inorganic Pt-click reactions enable synthesis of novel (potentially multimetallic) Pt complexes and provide plausible routes to introduce functional groups and monitoring Pt-azido drug localisation.     

Synthesis and characterization of new dinuclear complexes of molybdenum(V) with β′-hydroxy-β-enaminones

New dinuclear molybdenum(V) complexes have been obtained by the reaction of [Mo₂O₃(acac)₄] (acac=acetilacetonate ion) with the polydentate ligands, β′-hydroxy-β-enaminones. All prepared complexes consist of Mo₂O₄ ²⁺ core coordinated by two ligands as in the β-diketonates only through two donor oxygen atoms. Such bonding gives the opportunity for the sixth coordination place around molybdenum to be completed by the monodentate solvent molecule D. All compounds have been characterized by means of elemental analyses, one- and two-dimensional NMR spectroscopy, IR spectroscopy as well as by thermal analyses. The molecular and crystal structures of the molybdenum(V) complexes 1a and 1b coordinated by two different isomeric ligands as well as of the isomer a itself have been determined by a single crystal X-ray diffraction method.     

Synthesis and characterization of β-diketonato ruthenium(II) complexes with two 4-bromo or protected 4-ethynyl-2,2′-bipyridine ligands

Two new mononuclear mixed-ligand ruthenium(II) complexes with acetylacetonate ion (2,4-pentanedionate, acac) and functionalized bipyridine (bpy) in position 4, [Ru(bpyBr)₂(acac)](PF₆) (2; bpyBr = 4-Bromo-2,2′-bipyridine, acac = 2,4-pentanedionate ion) and [Ru(bpyOH)₂(acac)](PF₆) (3; bpyOH = 4-[2-methyl-3-butyn-2-ol]-2,2′-bipyridine) were prepared as candidates for building blocks. The ¹H NMR, ¹³C NMR, UV-Vis, electrochemistry and FAB mass spectral data of these complexes are presented.