The first nano-cocrystal formulation of marine drug cytarabine with uracil based on cocrystal nanonization strategy for long-acting injection exhibiting enhanced antitumor activity.

To emphasize the superiority of uracil (UR) in ameliorating biopharmaceutical characteristics of marine antitumor medicine cytarabine (ARA), thus gaining some innovative opinions for the exploitation of nanococrystal formulation, a cocrystal nanonization strategy is proposed by integrating cocrystallization and nanosize preparation techniques. For one thing, based on UR's unique structural features and natures together with advantages of preferential uptake by tumor cells, cocrystallizing ARA with UR is expected to improve the in vitro/vivo performances. For another, the nanonization procedure is oriented towards maintaining the long-term effective drug level. Along this route, a cocrystal of ARA with UR, viz., ARA-UR, is successfully synthesized and then transformed into nano-cocrystal. The cocrystal structure is precisely confirmed by various methods, demonstrating that a 1:1 ARA and UR in the crystal forms cytosine-UR hydrogen-bonding interactions, thus constructing supramolecular frameworks by strong π-π stacking interplays; while the nano-cocrystal is block-shaped particles of 562.70 nm with zeta potential -33.40 mV. The properties of cocrystal ARA-UR and its nano-cocrystal in vitro/vivo are comparatively explored by theoretical calculations and experimental analyses, revealing that permeability of both is significantly increased than ARA per se. Notably, the meliorative natures of both the cocrystal and nano-cocrystal in vitro bring excellent antitumor activity, but the latter has greater strengths over the former. More notably, the nano-cocrystal can sustain effective concentration for a relatively longer time, causing lengthened retention time and better absorption in vivo. The contribution offers a fire-new dosage form of ARA for long-lasting delivery, thus filling the vacancy in nanococrystal studies about marine drugs.

The first marine dual-drug cocrystal of cytarabine with 5-fluorouracil having synergistic antitumor effects shows superior biopharmaceutical peculiarities by oral administration.

In order to highlight the advantages of cocrystallization technique in perfecting in vitro/vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both "pyrimidine-pyrimidine" and "pyrimidine-sugar" cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC50. Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.

A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics.

To fully play the advantages of cocrystallization and nano-preparation techniques in regulating in vitro/vivo biopharmaceutical properties of anticancer drug 5-fluorouracil (FU), and further exploit new avenues in its formulation development, a recombination strategy of cocrystallization and nano-micellar self-assembly techniques is proposed. Thereinto, the cocrystallization technique is aiming at augmenting antitumor ability by ameliorating physicochemical performances of FU, while the nano-micellar self-assembly technique is mainly employed to achieve slowed release and long-term efficacy. Guided by this strategy, a new zwitterionic cocrystal of FU with L-proline (PL), FU-PL, is successfully synthesized, and then incorporated into carriers PEG-PCL to gain cocrystal micelles. The structure of FU-PL cocrystal and morphology of the cocrystal micelles are respectively characterized via various analytical means. The comparative studies of in vivo/vitro properties are systematacially conducted by theoretical and experimental methods. The results showcase that the cocrystal's solubility and permeability are 4.60 and 3.89 folds higher than those of pristine drug FU at pH 6.8, separately; and the drug loading and entrapment efficiency of the obtained cocrystal micelles with spherical particles of 146 nm are 2.39 and 1.74 times than those of FU micelles itself, respectively. Particularly, both the cocrystal and its micelles eventually bring about the excellent antitumor activity, but the cocrystal micelles improve even more significantly in comparison with the cocrystal. These in vitro advantages have promoted the in vivo absorption with increased relative bioavailability (FREL) of 2.72 relative to FU-PL cocrystal. More particularly, the cocrystal micelles have preferable sustained-release action relative to FU micelles, thus more efficaciously prolonging the half-life and therapy duration. All these findings not only supply a novice slow-release dosage form for FU with greater efficiency, but also fill the blank of the micelle researches for antitumor pharmaceutical cocrystals.

5-fluorouracil-caffeic acid cocrystal delivery agent with long-term and synergistic high-performance antitumor effects.

Aim: To explore how to transform cocrystals of the anticancer drug 5-fluorouracil (FL) with caffeic acid (CF; FL-CF-2H2O) into a nanoformulation, a self-assembly strategy of cocrystal-loaded micelles is proposed. Methods: Nanomicelles were assembled to deliver cocrystal FL-CF-2H2O with synergistic activity, and their in vitro/vivo properties were evaluated by combining theoretical and experimental methods. Result: More cocrystal was packed into the polymers due to the stronger interaction energy during micellar assembly, producing excellent cytotoxicity and pharmacokinetic behavior, especially synergistic abilities and long-term therapy. Conclusion: This case exemplifies the particular benefits of the self-assembly strategy of cocrystal-loaded micelles in keeping a delicate balance between long-term effects and high efficiency for FL, and offers a feasible technical scheme for cocrystal delivery agents for antitumor drugs.

To exemplify the feasibility of the cocrystal conversion of anticancer drug 5-fluorouracil (FL) with phenolic acid nutrient caffeic acid (CF) into a nanomicelle formulation, and further provide new options for the development of slowed-release cocrystal formulations with long-acting and synergistic antitumor effects, in this study, a cocrystalline complex of FL and CF (cocrystal FL-CF-2H₂O) was loaded into polymer PEG-PCL to successfully assemble the cocrystal nanomicelles by a self-assembly strategy. The morphology of the cocrystal nanomicelles was characterized, and in vitro/vivo properties were evaluated by combining theoretical with experimental methods. The results showed that the cocrystal nanomicelles with regular sphericity and homogeneous particle size had greater drug loading and entrapment efficiency than FL nanomicelles, which is also supported by theoretical predictions of the interaction energy between the cocrystal FL-CF-2H₂O and polymer PEG-PCL. The excellent encapsulation effects give rise to more potent cytotoxicity, better absorption and prolonged retention time in vivo. Relative to FL nanomicelles, the present cocrystal nanomicelles with synergistic antitumor abilities exhibited prominent slowed-release behavior that was more conducive to the long-term maintenance of therapeutic concentrations in vivo. The present case offers a feasible technical scheme for successful nanoformulation research on synergistic antitumor pharmaceutical cocrystals.

Supramolecular self-assembly and perfected in vitro/vivo property of 5-fluorouracil and ferulic acid on the strength of double optimized strategy: the first 5-fluorouracial-phenolic acid nutraceutical cocrystal with synergistic antitumor efficacy.

For highlighting the predominance of phenolic acid nutraceutical ferulic acid (FR) in regulating the in vivo/vitro performances of anticancer drug 5-fluorouracil (Flu) and strengthening their cooperativity in antitumor effect, thus achieving a major breakthrough in the development of drug-nutraceutical cocrystal with synergistic antitumor action, a cocrystallization strategy of dual optimization is created, in which both the in vivo and vitro natures of Flu are improved by exploiting the FR's excellent physicochemical property. Moreover, Flu's anticancer effects were promoted by exerting the assistant antitumor peculiarity of FR. Such dual optimization of FR for Flu in physicochemical properties and anticancer activities is beneficial for realizing synergistic augmentation effect by taking the benefit of the cooperativeness of Flu and FR in the anticancer ability. Based on this idea, a novel cocrystal of Flu and FR, namely, Flu-FR-H2O, is successfully assembled as the first 5-fluorouracil-nutraceutical cocrystal with synergistic antitumor effect and its explicit structure is resolved. The single-crystal X-ray diffraction demonstrates that Flu and FR have a ratio of 1 : 1 with one equivalent of solvent water in the cocrystal, where one-dimensional hydrogen-bonding helices and FR-Flu hydrogen-bonding pairs, together construct a three-dimensional supramolecular network. By combining experimental evaluation with theoretical analysis, in vitro/vivo pharmaceutical properties are scientifically investigated. Results show that the permeability and aqueous solubility of Flu are respectively elevated by 5.08 and 1.64 folds, which has brought about ameliorated pharmacokinetics, thus providing prolonged retention time and increased oral bioavailability. More interestingly, the cocrystal shows synergistic inhibition ability of Flu and FR against tested tumor cell strains, hence laying the groundwork for reducing the dosage and even the toxic side effects of Flu. As a result of this, the present research not only provides a new strategy for Flu to optimize its physicochemical properties and antitumor activities simultaneously but also offers some opinions for the development of synergistic antitumor pharmaceutical cocrystals.

Synthesis, structure, and biological active evaluation of a new cyclic tetranuclear copper(II) complex bridged both by oxamido and carboxylate groups.

A new tetracopper(II) complex bridged both by oxamido and carboxylato groups, namely [Cu4 (dmaepox)2 (bpy)2 ](NO3 )2 ·2H2 O, where H3 dmaepox and bpy represent N-benzoato-N'- (3-methylaminopropyl)oxamide and 2,2'-bipyridine, was synthesized, and its structure reveals the presence of a centrosymmetric cyclic tetracopper(II) cation assembled by a pair of cis-dmaepox3- - bridged dicopper(II) units through the carboxylato groups, in which the endo- and exo-copper(II) ions bridged by the oxamido group have a square-planar and a square-pyramidal coordination geometries, respectively. The aromatic packing interactions assemble the complex molecules to a two-dimensional supramolecular structure. The reactivity toward DNA and protein bovine serum albumin (BSA) indicates that the complex can interact with herring sperm DNA through the intercalation mode and the binding affinity is dominated by the hydrophobicity and chelate ring arrangement around copper(II) ions and quenches the intrinsic fluorescence of BSA via a static process. The cytotoxicity of the complex shows selective cancer cell antiproliferative activity.

Synthesis and structure of a new trinuclear nickel(II) complex bridged by N-[3-(Dimethylamino)propyl]-N'-(2-hydroxyphenyl)oxamido: in vitro anticancer activities, and reactivities toward DNA and protein.

A new trinickel(II) complex bridged by N-[3-(dimethylamino)propyl]- N'-(2-hydroxylphenyl)oxamido (H3 pdmapo), namely [Ni3 (pdmapo)2 (H2 O)2 ]⋅4CH3 OH, was synthesized and characterized by X-ray single-crystal diffraction and other methods. In the molecule, two symmetric cis-pdmapo3- mononickel(II) complexes as a "complex ligand" using the carbonyl oxygen atoms coordinate to the center nickel(II) ion situated on an inversion point. The Ni···Ni distance through the oxamido bridge is 5.2624(4) Å. The center nickel(II) ion and the lateral ones have octahedral and square-planar coordination geometries, respectively. In the crystal, a three-dimensional supramolecular network dominated by hydrogen bonds is observed. The reactivity toward DNA/protein bovine serum albumin (BSA) revealed that the complex could interact with herring sperm DNA (HS-DNA) through the intercalation mode and quench the intrinsic fluorescence of BSA via a static mechanism. The in vitro anticancer activities suggested that the complex is active against the selected tumor cell lines.

Synthesis and structure of new tetracopper(II) complexes with N-benzoate-N'-[3-(diethylamino)propyl]oxamide as a bridging ligand: The influence of hydrophobicity on enhanced DNA/BSA-binding and anticancer activity.

Two new tetracopper(II) complexes bridged by N-benzoate-N'-[3-(diethylamino)propyl]oxamide (H3bdpox), and ended with 4,4'-dimethyl-2,2'-bipyridine (Me2bpy) or 2,2'-bipyridine (bpy), namely [Cu4(bdpox)2(Me2bpy)2](pic)2 (1) and [Cu4(bdpox)2(bpy)2](pic)2·2H2O (2) (where pic denotes the picrate anion) have been synthesized and characterized by X-ray single-crystal diffraction and other methods. In both complexes, four copper(II) ions are bridged alternately by the cis-oxamido and the carboxylato groups of two bdpox(3-) ligands to form a centrosymmetric cyclic tetranuclear cation, in which, the copper(II) ions at the endo- and exo-sites of cis-bdpox(3-) ligand have square-planar and square-pyramidal coordination geometries, respectively. The reactivity towards DNA/BSA suggests that these complexes can interact with HS-DNA through the intercalation mode and the binding affinity varies as 1>2 depending on the hydrophobicity, and effectively quench the fluorescence of protein BSA via a static mechanism. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA-binding affinity.

Synthesis and structure elucidation of new µ-oxamido-bridged dicopper(II) complex with in vitro anticancer activity: A combined study from experiment verification and docking calculation on DNA/protein-binding property.

A new oxamido-bridged dicopper(II) complex with formula of [Cu2(deap)(pic)2], where H2deap and pic represent N,N'-bis[3-(diethylamino)propyl]oxamide and picrate, respectively, was synthesized and characterized by elemental analyses, molar conductance measurements, IR and electronic spectral study, and single-crystal X-ray diffraction. The crystal structure analyses revealed that the two copper(II) atoms in the dicopper(II) complex are bridged by the trans-deap(2-) ligand with the distances of 5.2116(17)Å, and the coordination environment around the copper(II) atoms can be described as a square-planar geometry. Hydrogen bonding and π-π stacking interactions link the dicopper(II) complex into a three-dimensional infinite network. The DNA/protein-binding properties of the complex are investigated by molecular docking and experimental assays. The results indicate that the dicopper(II) complex can interact with HS-DNA in the mode of intercalation and effectively quench the intrinsic fluorescence of protein BSA by 1:1 binding with the most possible binding site in the proximity of Trp134. The in vitro anticancer activities suggest that the complex is active against the selected tumor cell lines, and IC50 values for SMMC-7721 and HepG2 are lower than cisplatin. The effects of the electron density distribution of the terminal ligand and the chelate ring arrangement around copper(II) ions bridged by symmetric N,N'-bis(substituted)oxamides on DNA/BSA-binding ability and in vitro anticancer activity are preliminarily discussed.

Synthesis and structure elucidation of new µ-oxamido-bridged dicopper(II) complexes showing in vitro anticancer activity: Evaluation of DNA/protein-binding properties by experiment and molecular docking.

Two new µ-oxamido-bridged dicopper(II) complexes formulated as [Cu2(hmdoxd)(H2O)(Me2bpy)]-(ClO4)·DMF (1) and [Cu2(hmdoxd)(bpy)](ClO4)·CH3OH (2), where H3hmdoxd is N-(2-hydroxy-5-methylphenyl)-N'-[2-(dimethylamino)ethyl]oxamide; Me2bpy and bpy stand for 4,4'-dimethyl-2,2'-bipyridine and 2,2'-bipyridine, respectively, were synthesized and structurally characterized. The single-crystal X-ray diffraction analysis reveals that the copper(II) ions in complexes 1 and 2 are bridged by the cis-hmdoxd(3-) with corresponding Cu⋯Cu separations of 5.1596(6) and 5.1562(6) Å, respectively, in which the endo- and exo-copper(II) ions are located in square-planar and square-pyramidal geometries, respectively, for 1, and square-planar environments for 2. In the crystals of the two complexes, there are abundant hydrogen bonds and π-π stacking interactions contributing to the supramolecular structure. The DNA/protein-binding property of the two complexes are studied both theoretically and experimentally, indicating that complexes 1 and 2 can interact with DNA in the mode of intercalation and partial intercalation, respectively, and effectively bind to protein BSA via the favored binding sites Trp213 for 1 and Trp134 for 2. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA/protein-binding affinities following the order of 1>2. The effect of the hydrophobicity of both the bridging and terminal ligands in the dicopper(II) complexes on DNA/protein-binding events and in vitro anticancer activities is preliminarily discussed.

Synthesis and structure of new dicopper(II) complexes bridged by N-(2-hydroxy-5-methylphenyl)-N'-[3-(dimethylamino)propyl]oxamide with in vitro anticancer activity: A comparative study of reactivities towards DNA/protein by molecular docking and experimental assays.

Two new dicopper(II) complexes bridged by N-(2-hydroxy-5-methylphenyl)-N'-[3-(dimethyl-amino)propyl]oxamide (H3hmpoxd), and end-capped with 4,4'-dimethyl-2,2'-bipyridine (Me2bpy) and 2,2'-bipyridine (bpy), were synthesized and structurally characterized, namely [Cu2(hmpoxd)(CH3OH)(Me2bpy)](ClO4) (1) and [Cu2(hmpoxd)(bpy)](ClO4)∙CH3OH (2). The single-crystal X-ray diffraction analysis reveals that the endo- and exo-copper (II) ions bridged by the cis-hmpoxd(3-) ligand are located in square-planar and square-pyramidal geometries, respectively, for 1, and square-planar environments in 2. The DNA/protein-binding natures are studied theoretically and experimentally, indicating that both the two complexes can interact with the DNA in the mode of intercalation, and effectively quench the intrinsic fluorescence of protein BSA via the favored binding sites Trp213 for 1 and Trp134 for 2. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA/BSA-binding affinities following the order of 1 > 2. The synergistic hydrophobicity of the bridging and terminal ligands in these complexes on DNA/BSA-binding events and in vitro anticancer activities is preliminarily discussed.

Synthesis and crystal structure of new dicopper(II) complexes having asymmetric N,N'-bis(substituted)oxamides with DNA/protein binding ability: In vitro anticancer activity and molecular docking studies.

Two new dicopper(II) complexes bridged by asymmetric N,N'-bis(substituted)oxamide ligands: N-(5-chloro-2-hydroxyphenyl)-N'-[2-(dimethylamino)ethyl]oxamide (H3chdoxd) and N-hydroxypropyl-N'-(2-carboxylatophenyl)oxamide (H3oxbpa), and end-capped with 2,2'-bipyridine (bpy), namely [Cu2(ClO4)(chdoxd)(CH3OH)(bpy)]·H2O (1) and [Cu2(pic)(oxbpa)(CH3OH)(bpy)]·0.5CH3OH (2) (pic denotes picrate anion), have been synthesized and characterized by elemental analysis, molar conductivity measurement, IR and electronic spectral studies, and single-crystal X-ray diffraction. The X-ray diffraction analysis revealed that both the copper(II) ions bridged by the cis-oxamido ligands in dicopper(II) complexes 1 and 2 are all in square-pyramidal environments with the corresponding Cu⋯Cu separations of 5.194(3) and 5.1714(8)Å, respectively. In the crystals of the two complexes, there are abundant hydrogen bonds and π-π stacking interactions contributing to the supramolecular structure. The reactivities toward herring sperm DNA (HS-DNA) and bovine serum albumin (BSA) of the two complexes are studied both theoretically and experimentally, indicating that both the two complexes can interact with the DNA in the mode of intercalation, and effectively bind to BSA via the favored binding sites Trp134 for the complex 1 and Trp213 for the complex 2. Interestingly, the in vitro anticancer activities of the two complexes against the selected tumor cell lines are consistent with their DNA/BSA-binding affinities following the order of 1>2. The effects of coordinated counterions in the two complexes on DNA/BSA-binding ability and in vitro anticancer activity are preliminarily discussed.

Synthesis and Structure of a New Copper(II) Coordination Polymer Alternately Bridged by Oxamido and Carboxylate Groups: Evaluation of DNA/BSA Binding and Cytotoxic Activities.

A new one-dimensional (1D) copper(II) coordination polymer {[Cu2 (dmaepox)(dabt)](NO3) · 0.5 H2 O}n , where H3 dmaepox and dabt denote N-benzoato-N'-(3-methylaminopropyl)oxamide and 2,2'-diamino-4,4'-bithiazole, respectively, was synthesized and characterized by single-crystal X-ray diffraction and other methods. The crystal structure analysis revealed that the two copper(II) ions are bridged alternately by cis-oxamido and carboxylato groups to form a 1-D coordination polymer with the corresponding Cu · · · Cu separations of 5.1946(19) and 5.038(2) Å. There is a three-dimensional supramolecular structure constructed by hydrogen bonding and π-π stacking interactions in the crystal. The reactivity towards herring sperm DNA (HS-DNA) and bovine serum albumin (BSA) indicated that the copper(II) polymer can interact with the DNA in the mode of intercalation, and bind to BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The in vitro cytotoxicity suggested that the copper(II) polymer exhibits cytotoxic effects against the selected tumor cell lines.

Synthesis and structure of dicopper(II) complexes bridged by N-(5-chloro-2-hydroxyphenyl)-N'-[3-(methy lamino)propyl]oxamide: evaluation of DNA/protein binding, DNA cleavage, and in vitro anticancer activity.

Three new dicopper(II) complexes bridged by N-(5-chloro-2-hydroxyphenyl)-N'-[3-(methylamino)-propyl]oxamide (H3chmpoxd) and end-capped with 1,10-phenanthroline (phen); 2,2'-diamino-4,4'-bithiazole (dabt); and 2,2'-bipyridine (bpy), namely [Cu2(chmpoxd)(H2O)(phen)](ClO4)⋅CH3CN (1), [Cu2(chmpoxd)(dabt)(C2H5OH)](NO3) (2) and [Cu2(chmpoxd)(H2O)(bpy)](NO3)⋅CH3CN (3), were synthesized and structurally characterized. The single-crystal X-ray diffraction analysis revealed that both the copper(II) ions bridged by the cis-chmpoxd(3-) ligands in the three complexes are in square-planar and square-pyramidal environments, respectively. The reactivity towards herring sperm DNA (HS-DNA) and protein bovine serum albumin (BSA) indicated that these copper(II) complexes can interact with the DNA in the mode of intercalation, and bind to BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The cytotoxicity and DNA cleavage suggested that all the dicopper(II) complexes are active against the selected tumor cell lines, and the complex 1 exhibits the cleavage capacity for plasmid DNA.

Synthesis and Structure of a Ternary Copper(II) Complex with Mixed Ligands of Diethylenetriamine and Picrate: DNA/Protein-Binding Property and In Vitro Anticancer Activity Studies.

Based on the importance of the design and synthesis of transition metal complexes with noncovalent DNA/protein-binding abilities in the field of metallo pharmaceuticals, a new mononuclear ternary copper(II) complex with mixed ligands of diethylenetriamine (dien) and picrate anion (pic), identified as [Cu(dien)(pic)](pic), was synthesized and characterized by elemental analysis, molar conductivity measurement, infrared spectrum, electronic spectral studies, and single-crystal X-ray diffractometry. The structure analysis reveals that the copper(II) complex crystallizes in the monoclinic space group P21 /c, and the copper(II) ion has a distorted square pyramidal coordination geometry. A two-dimensional supramolecular structure is formed through hydrogen bonds. The DNA/bovine serum albumin (BSA)-binding properties of the complex are explored, indicating that the complex can interact with herring sperm DNA via intercalation mode and bind to BSA responsible for quenching of tryptophan fluorescence by static quenching mechanism. The in vitro anticancer activity shows that the copper(II) complex is active against the selected tumor cell lines.

Synthesis and crystal structure of new dicopper(II) complexes with N,N'-bis-(dipropylenetriamine)oxamide as bridging ligand: effects of the counterions on DNA/protein-binding property and in vitro antitumor activity.

Two new dicopper(II) complexes bridged by N,N'-bis(dipropylenetriamine)oxamide (H2oxdipn), namely, [Cu2(oxdipn)](pic)2(1) and [Cu2(oxdipn)(ClO4)2] (2), where pic represents picrate ion, have been synthesized and characterized by elemental analyses, molar conductance measurements, IR and electronic spectral studies, and X-ray single crystal diffraction. In both dicopper(II) complexes, the two copper(II) ions are bridged by trans-oxdipn ligand with the Cu⋯Cu separations of 5.2536(15) and 5.231(2)Å, respectively. The copper(II) ion in complex 1 has a square-planar coordination geometry, while that in 2, a square-pyramidal. Linked with classical hydrogen bonds, the molecules of complex 1 consist of a one-dimensional chain, while complex 2 molecules result in a two-dimensional structure. Numerous hydrogen bonds link complex 1 or 2 into a 2-D infinite network. In vitro cytotoxicity experiment shows that the two dicopper(II) complexes exhibit cytotoxic effects against the selected tumor cell lines. The reactivity towards herring sperm DNA (HS-DNA) and bovine serum albumin (BSA) reveals that the two dicopper(II) complexes can interact with the DNA in the mode of intercalation, and effectively quench the intrinsic fluorescence of BSA via a static mechanism. The influence of different counterions in this kind of dicopper(II) complexes on DNA/BSA-binding properties, and the in vitro cytotoxic activities was investigated.

In vitro cytotoxic activities, DNA-, and BSA-binding studies of a new dinuclear copper(II) complex with N-[3-(dimethylamino)propyl]-N'-(2-carboxylatophenyl)-oxamide as ligand.

A new dinuclear copper(II) complex bridged by N-[3-(dimethylamino)propyl]-N'- (2-carbo-xylatophenyl)oxamide (H3 dmapob), and endcapped with 2,2'-diamino-4,4'-bithiazole (dabt), namely [Cu2(dmapob)(dabt)(CH3OH)(pic)]·(DMF)0.75 ·(CH3OH)0.25 has been synthesized and characterized by elemental analysis, molar conductivity measurement, infrared and electronic spectra studies, and single-crystal X-ray diffraction. In the crystal structure, both copper(II) ions have square-pyramidal coordination geometries. The Cu···Cu separation through the oxamido bridge is 5.176(9) Å. A two-dimensional supramolecular framework is formed through hydrogen bonds and π-π stacking interactions. The reactivities toward herring sperm DNA and bovine serum albumin (BSA) show that the complex can interact with the DNA via intercalation mode and bind to the BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The in vitro anticancer activities suggest that the copper(II) complex is active against the selected tumor cell lines. The influence of different bridging ligands in dinuclear complexes on the DNA- and BSA-binding properties as well as anticancer activities is preliminarily discussed.

Syntheses and crystal structures of tetracopper(II) complexes bridged by asymmetric N,N'-bis(substituted)oxamides: Molecular docking, DNA-binding and in vitro anticancer activity.

Two new tetranuclear copper(II) complexes of the formulae [Cu4(oxbm)2(phen)2](NO3)2⋅6H2O (1) and [Cu4(oxbpa)2(phen)2](ClO4)2·4H2O (2), where H3oxbm and H3oxbpa stand for N-(2-aminopropyl)-N'- (2-carboxylatophenyl)oxamide and N-hydroxypropyl-N'-(2-carboxylatophenyl)oxamide, respectively, and phen is 1,10-phenanthroline, have been synthesized and characterized by elemental analyses, molar conductivity measurements, IR and electronic spectrum studies, and X-ray single crystal diffraction. In the two tetracopper(II) complexes, the presence of the circular tetracopper(II) cations is assembled by a pair of cis-oxamido-bridged dicopper(II) units through carboxyl bridges, in which Cu1 is located in a distorted square-planar environment, while Cu2 is in a distorted square-pyramidal geometry. Numerous hydrogen bonds link complex 1 or 2 into a 2-D infinite network. The interactions of the two tetracopper(II) complexes with DNA are investigated both theoretically and experimentally, revealing that these tetracopper(II) complexes can interact with HS-DNA in the mode of intercalation, and complex 1 possesses stronger intercalating ability. The molecular docking of the two tetranuclear copper(II) complexes with the self-complementary DNA duplex of sequence d(ACCGACGTCGGT)2 facilitates the binding events. Cytotoxicity experiments indicate that the two tetracopper(II) complexes exhibit cytotoxic effects against human hepatocellular carcinoma cell SMMC-7721 and human lung adenocarcinoma cell A549. Interestingly, the cytotoxic activities of the two tetracopper(II) complexes are consistent with their DNA-binding abilities, following the order of 1>2. The main results suggest that different bridging ligands in tetracopper(II) complexes may play an important role in the DNA-binding properties and cytotoxic activities.

Synthesis and crystal structure of binuclear copper(II) complex bridged by N-(2-hydroxyphenyl)-N'-[3-(diethylamino)propyl]oxamide: in vitro anticancer activity and reactivity toward DNA and protein.

A new oxamido-bridged bicopper(II) complex, [Cu2(pdpox)(bpy)(CH3OH)](ClO4), where H3pdpox and bpy stand for N-(2-hydroxyphenyl)-N'-[3-(diethylamino)propyl]oxamide and 2,2'-bipyridine, respectively, has been synthesized and characterized by elemental analyses, molar conductivity measurements, infrared and electronic spectra studies, and X-ray single crystal diffraction. In the crystal structure, the pdpox(3-) ligand bridges two copper(II) ions as cisoid conformation. The inner copper(II) ion has a {N3O} square-planar coordination geometry, while the exo- one is in a {N2O3} square-pyramidal environment. There are two sets of interpenetrating two-dimensional hydrogen bonding networks parallel to the planes (2 1 0) and (21¯0), respectively, to form a three-dimensional supramolecular structure. The bicopper(II) complex exhibits cytotoxic activity against the SMMC7721 and A549 cell lines. The reactivity toward herring sperm DNA and bovine serum albumin revealed that the bicopper(II) complex can interact with the DNA by intercalation mode, and the complex binds to protein BSA responsible for quenching of tryptophan fluorescence by static quenching mechanism.

Syntheses and structures of new trimetallic complexes bridged by N-(5-chloro-2-hydroxyphenyl)-N'-[3-(dimethylamino)propyl]oxamide: cytotoxic activities, and reactivities towards DNA and protein.

Two new µ-oxamido-bridged trinuclear complexes, namely [Cu(3)L(2)(H(2)O)(2)]{[Cu(3)L(2)]·2H(2)O}(2) (1) and [Ni(3)L(2)(H(2)O)(DMF)](H(2)O)(DMF) (2), where L(3-) is deprotonated N-(5-chloro-2-hydroxyphenyl)-N'-[3-(dimethylamino)propyl]oxamide, have been synthesized and characterized by X-ray single-crystal diffraction. The structure of complex 1, which consists of three tricopper(II) neutral molecules, lies on an inversion centre at Cu5 atom and thus has a trans conformation. The structure of complex 2 composes of a trinickel(II) neutral molecule. In vitro cytotoxic activities, and the reactivities of the two complexes towards DNA and protein are investigated. Cytotoxicities experiments reveal that the two trinuclear complexes both exhibits cytotoxic effects against human hepatocellular carcinoma cell SMMC-7721 and human lung adenocarcinoma cell A549. The interactions of the two complexes with herring sperm DNA (HS-DNA) are investigated by using UV absorption and fluorescence spectra and viscometry. The results suggested that both of the two trinuclear complexes could interact with HS-DNA through the intercalation mode and follow the binding affinity order of 1>2. The reactivity towards protein BSA revealed that the quenching of BSA fluorescence by the two complexes are static quenching, and complex 1 exhibits a higher BSA-binding ability than that of complex 2.