Sialic acid detection and theranostic activity of phenylboronic acid-based fluorescent probe in human colorectal adenocarcinoma HT-29 cells.

A new probe, 4-(((3',6'-bis(diethylamino)-3-oxospiro[isoindoline-1,9'-xanthen]-2-yl)imino)methyl)phenyl)boronic acid (R4B) was prepared by facile condensation of 4-formylphenylboronic acid and rhodamine B hydrazide. R4B was characterized by spectroscopic methods and single crystal X-ray diffraction. The sensor R4B solution turned pink and emitted orange fluorescence only in the presence of sialic acid but remained colorless and non-fluorescent otherwise. The sugar recognition performance was investigated via UV-vis and fluorescence spectroscopic studies. Our results revealed that R4B has good affinity and selectivity for sialic acid over common monosaccharides, with a detection limit as low as 10-7 M. Furthermore, R4B selectively inhibited growth of human colorectal adenocarcinoma HT-29 (IC50 <20 µM) without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with R4B suppressed HT-29 colony formation via mitochondrial apoptosis in a time-dependent manner. Cellular imaging studies also revealed the ability of R4B as a fluorescence dye to detect intracellular sialic acid and showed mitochondria-tracking ability in HT-29 cells. In summary, R4B is a potential theranostic for the detection of intracellular sialic acid during the early incubation period, followed by induction of cancer apoptotic cell death at a later treatment point.

Synthesis, Structural Characterization, Hirshfeld Surface Analysis, and Antibacterial Study of Pd(II) and Ni(II) Schiff Base Complexes Derived from Aliphatic Diamine.

A Schiff base bearing two methyl substituents, namely, 6,6'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl) bis(azanylylidene)) bis(methanylylidene)) bis(2-methylphenol) [H2AD1Me] was synthesized and characterized through physicochemical and spectroscopic analyses. Then, the Schiff base was complexed with Pd(II) and Ni(II) to form [Pd(AD1Me)] and [Ni(AD1Me)], respectively. Both metal complexes were successfully obtained and characterized through several analyses, viz., melting point, elemental analysis, molar conductivity, magnetic susceptibility, FTIR, 1H NMR, UV-vis, and single crystal X-ray diffraction. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. Both metal complexes were crystallized in a monoclinic crystal system with the space group of P21/c. Additionally, the deprotonated phenolic oxygen atom (O1/O2) and azomethine nitrogen atom (N1/N2) of the ligand chelate the Pd(II) and Ni(II) ions, forming a slightly distorted square-planar complex containing three six-membered rings encircling the metal core with dsp2 hybridization. The shift of ν(C=N) to a higher frequency in FTIR by 26-28 cm-1 indicated that the complexation to Pd(II) and Ni(II) through the azomethine N was established. It was further supported through the shifting of the azomethine proton signal to higher or lower chemical shifts with Δδ = 0.43-1.15 ppm in 1H NMR. In addition, the shifting of the n-π*(C=N) band in UV-vis spectra with Δλ = 24-40 nm indicated the involvement of azomethine nitrogen in the complexation. All the compounds showed no significant antibacterial activity against three bacterial strains, namely, Staphylococcus aureus subsp. aureus Rosenbach (ATCC 6538), Streptococcus mutans Clarke (ATCC 700,610), and Proteus vulgaris (ATCC 6380), as the percent growth inhibition calculated was less than 90%.

Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action.

BACKGROUND: Malaria remains one of the most virulent and deadliest parasitic disease in the world, particularly in Africa and Southeast Asia. Widespread occurrence of artemisinin-resistant Plasmodium falciparum strains from the Greater Mekong Subregion is alarming. This hinders the national economies, as well as being a major drawback in the effective control and elimination of malaria worldwide. Clearly, an effective anti-malarial drug is urgently needed. METHODS: The dinuclear and mononuclear copper(II) and zinc(II) complexes were synthesized in ethanolic solution and characterized by various physical measurements (FTIR, CHN elemental analysis, solubility, ESI-MS, UV-Visible, conductivity and magnetic moment, and NMR). X-ray crystal structure of the dicopper(II) complex was determined. The in vitro haemolytic activities of these metal complexes were evaluated spectroscopically on B+ blood while the anti-malarial potency was performed in vitro on blood stage drug-sensitive Plasmodium falciparum 3D7 (Pf3D7) and artemisinin-resistant Plasmodium falciparum IPC5202 (Pf5202) with fluorescence dye. Mode of action of metal complexes were conducted to determine the formation of reactive oxygen species using PNDA and DCFH-DA dyes, JC-1 depolarization of mitochondrial membrane potential, malarial 20S proteasome inhibition with parasite lysate, and morphological studies using Giemsa and Hoechst stains. RESULTS: Copper(II) complexes showed anti-malarial potency against both Pf3D7 and Pf5202 in sub-micromolar to micromolar range. The zinc(II) complexes were effective against Pf3D7 with excellent therapeutic index but encountered total resistance against Pf5202. Among the four, the dinuclear copper(II) complex was the most potent against both strains. The zinc(II) complexes caused no haemolysis of RBC while copper(II) complexes induced increased haemolysis with increasing concentration. Further mechanistic studies of both copper(II) complexes on both Pf3D7 and Pf5202 strains showed induction of ROS, 20S malarial proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis. CONCLUSION: The dinuclear [Cu(phen)-4,4'-bipy-Cu(phen)](NO3)4 is highly potent and can overcome the total drug-resistance of Pf5202 towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive Pf3D7, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets.

A rhodamine based chemosensor for solvent dependent chromogenic sensing of cobalt (II) and copper (II) ions with good selectivity and sensitivity: Synthesis, filter paper test strip, DFT calculations and cytotoxicity.

A new chemosensor 1 was synthesized by reacting rhodamine B hydrazide and 2,3,4-trihydroxybenzaldehyde, which was then characterized by spectroscopic techniques and single crystal X-ray crystallography. Sensor 1 has the ability to sense Co2+/Cu2+ ions by "naked-eye" with an apparent colour change from colourless to pink in different solvent system, MeCN and DMF respectively. Furthermore, it can selectively detect Co2+/Cu2+ among wide range of different metal ions, and it exhibits low detection limit of 4.425 × 10-8 M and 1.398 × 10-7 M respectively. Binding mode of the two complexes were determined to be 1:1 stoichiometry for Co2+ complex and 1:2 stoichiometry for Cu2+ complex through Job's plot, IR spectroscopy, mass spectrometry and 1H NMR spectroscopy. Moreover, reversibility of the sensor 1 as copper (II) ion detector was determined by using EDTA and the results showed that sensor 1 can be reused for at least 6 cycles. Other than that, a low cost chemosensor test strips were fabricated for the convenient "naked-eye" detection of Co2+ and Cu2+ in pure aqueous media. The MTT assay was conducted in order to determine the cytotoxicity of sensor 1 towards human cell lines.

Nickel and zinc complexes of testosterone N4-substituted thiosemicarbazone: Selective cytotoxicity towards human colorectal carcinoma cell line HCT 116 and their cell death mechanisms.

Two new Schiff base ligands (TE and TF) were prepared from conjugation of testosterone with 4-(4-ethylphenyl)-3-thiosemicarbazide and 4-(4-fluorophenyl)-3-thiosemicarbazide, respectively. Their nickel (NE and NF) and zinc (ZE and ZF) complexes were reported. X-ray crystallography revealed a distorted square planar geometry was adopted by NE. The compounds demonstrated excellent selectivity towards the colorectal carcinoma cell line HCT 116 despite their weak preferences towards the prostate cancer cell lines (PC-3 and LNCaP). Against HCT 116, all these compounds were able to arrest cell cycle at G0/G1 phase and induce apoptosis via mitochondria-dependent (TE, NE, and TF) and extrinsic apoptotic pathway (ZE, NF, and ZF). Moreover, only ZE was able to act as topoisomease I poison and halt its enzymatic reactions although all compounds presented excellent affinity towards DNA.

Thiosemicarbazone Derivative Induces in vitro Apoptosis in Metastatic PC-3 Cells via Activation of Mitochondrial Pathway.

BACKGROUND: Thiosemicarbazone (TSC) is a Schiff base that has been receiving considerable attention owing to its promising biological implication and remarkable pharmacological properties. The most promising drug candidate of this class would be Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) which has entered phase II clinical trials as a potent anti-cancer chemotherapeutic agent. OBJECTIVE: The current research aimed to synthesize several Schiff base ligands from (3-formyl-4-hydroxyphenyl) methyltriphenylphosphonium (T). Additionally, the current research aimed to study the growth inhibitory effect of triphenylphosphonium containing thiosemicarbazone derivatives on PC-3 cells by deciphering the mechanisms involved in cell death. METHOD: The compounds were characterized by various spectroscopic methods (infrared spectra, 1H NMR, 13C NMR, HRESIMS and X-ray crystallography) and the results were in conformity with the structure of the targeted compounds. Growth inhibitory effect of the compounds were performed against six human cell lines. RESULTS: DM(tsc)T displayed most potent activity against PC-3 cells with IC50 value of 2.64 ± 0.33 µM, surpassing that of the positive control cisplatin (5.47 ± 0.06 µM). There were marked morphological changes observed in DM(tsc)T treated cells stained with acridine orange and ethidium bromide which were indicative of cell apoptosis. Treatment with DM(tsc)T showed that the cell cycle is arrested in the G0/G1 phase after 72 hours. Mitochondrial membrane potential loss was observed in cells treated with DM(tsc)T, indicating the apoptosis could be due to mitochondria mediated pathway. CONCLUSION: This study indicates that DM(tsc)T would serve as a lead scaffold for rational anticancer agent development.

Topoisomerase I inhibition and DNA cleavage by zinc, copper, and nickel derivatives of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol complexes exhibiting anti-proliferation and anti-metastasis activity.

Three transition metal derivatives (Zn, Cu, and Ni) of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol (L) were synthesized by the reaction of the metal salts with the Schiff base ligand in one pot. In the crystal structure of [Zn(L)Br], the Schiff base ligand binds to the metal center through its phenolate oxygen and imine nitrogen, and adopts a distorted tetrahedral geometry. These compounds were found to inhibit topoisomerase I (topo I) activity, induce DNA cleavage and show DNA binding activity. Moreover, these compounds were found to be cytotoxic towards several cancer cell lines (A2780, MCF-7, HT29, HepG2, A549, PC3, LNCaP) and prevent metastasis of PC3. Collectively, Cu(II) complex 2 shows superior activity relative to its Zn(II) and Ni(II) analogs.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP).

Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

Copper complexes with phosphonium containing hydrazone ligand: topoisomerase inhibition and cytotoxicity study.

Four new copper(II) complexes containing phosphonium substituted hydrazone (L) with the formulations [CuL]Cl(3), [Cu(phen)L]Cl(4), [Cu(bpy)L]Cl(5), [Cu(dbpy)L]Cl(6), (where L = doubly deprotonated hydrazone; phen = 1,10'-phenanthroline; bpy = 2,2'-bipyridine; dbpy = 5,5'-dimethyl-2,2'-bipyridine) have been synthesized. The compounds were characterized by elemental analysis, spectroscopic methods and in the case of crystalline products by X-ray crystallography. The cytotoxicity and topoisomerase I (topo I) inhibition activities of these compounds were studied. It is noteworthy that the addition of N,N-ligands to the copper(II) complex lead to the enhancement in the cytotoxicity of the compounds, especially against human prostate adenocarcinoma cell line (PC-3). Complex 4 exhibits the highest activity against PC-3 with the IC50 value of 3.2 µΜ. The complexes can also inhibit topo I through the binding to DNA and the enzyme.

Zinc (II) complex with a cationic Schiff base ligand: synthesis, characterization, and biological studies.

A cationic Schiff base ligand, TSB (L) and its Zn (II) complex (1) were synthesized and characterized by using CHN, (1)H-NMR, FT-IR, UV, LC-MS, and X-ray methods. Their ability to inhibit topoisomerase I, DNA cleavage activities, and cytotoxicity were studied. X-ray diffraction study shows that the mononuclear complex 1 is four coordinated with distorted tetrahedral geometry. The singly deprotonated Schiff base ligand L acts as a bidentate ON-donor ligand. Complexation of L increases the inhibitory strength on topoisomerase I activity. Complex 1 could fully inhibit topoisomerase I activity at 250 µM, while L did not show any inhibitory effect on topoisomerase I activity. In addition, L and complex 1 could cleave pBR322 DNA in a concentration and time dependent profile. Surprisingly, L has better DNA cleavage activity than complex 1. The cleavage of DNA by complex 1 is altered in the presence of hydrogen peroxide. Furthermore, L and complex 1 are mildly cytotoxic towards human ovarian cancer A2780 and hepatocellular carcinoma HepG2.

[3-({(E)-2-[(4-Fluorophenyl)carbamo-thioyl]hydrazinylidene}methyl)-4-hy-droxy-benzyl]methyl-triphenyl-phos-phonium chloride.

The cation in the title salt, C(33)H(28)FN(3)OPS(+)·Cl(-), is highly twisted with the phospho-nium group occupying a position almost normal to the central hydroxyl-benzene ring [P-C-C-C tosrsion angle = -100.9 (3)°], and with the hydrazone substituent twisted out of the plane [C-C-C-N torsion angle = 13.1 (4)°]. The fluoro-benzene ring is twisted out of the plane of the adjacent thio-urea residue, forming a dihedral angle of 51.69 (10)°. The configuration about the C=N bond [1.281 (4) Å] is E, the O-H and N-H hydrogen atoms are syn, and in the thio-urea residue, the N-H hydrogen atoms are anti, allowing for the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, dimeric aggregates mediated by N-H⋯S bonds are formed, which are linked to the Cl(-) anions by O-H⋯Cl hydrogen bonds. The four-component aggregates are linked into a three-dimensional structure by C-H⋯Cl inter-actions.

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid.

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline-kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.

Bis(µ-5-hydr-oxy-2-{[2-(N-phenyl-thio-carbamo-yl)hydrazin-1-yl-idene]meth-yl}phenolato)bis[chloridozinc(II)] N,N-dimethyl-formamide tetra-solvate.

In the dinuclear title compound, [Zn(2)(C(14)H(12)N(3)O(2)S)(2)Cl(2)]·4C(3)H(7)NO, the two monodeprotonated Schiff base ligands N,O,S:O-chelate to Zn atoms. The formally negatively charged O atom involved in chelation also serves as a bridge. The O, O', N and S atoms comprise a square, and the Cl atom the apex of a square pyramid surrounding each metal atom. The solvate dimethyl-formamide mol-ecules, one of which is disordered over two positions in a 3:1 ratio, are hydrogen bonded to the dinuclear mol-ecule.

Bis[(4-chloro-benz-yl)triphenyl-phospho-nium] tetra-chloridozincate(II) trihydrate.

The crystal structure of the title compound, (C(25)H(21)ClP)(2)[ZnCl(4)]·3H(2)O, consists of tetra-hedral phosphonium cations and tetra-hedral zincate anions; the water mol-ecules form weak hydrogen bonds to the anions. Two of the water mol-ecules are disordered over three sites in a 0.68:0.55:0.77 ratio.

2,4,6,8-Tetra-kis(4-ethyl-phen-yl)-3,7-diaza-bicyclo-[3.3.1]nonan-9-one.

The bicyclo-[3.3.1]nonane ring in the title compound, C(39)H(44)N(2)O, adopts a chair-boat conformation with the four benzene rings being directed away from the carbonyl group. The presence of C-H⋯O contacts leads to helical supra-molecular chains along the b axis.

4-[(3,4-Dimeth-oxy-benzyl-idene)amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

The imino-carbon double-bond in the title Schiff base, C(20)H(21)N(3)O(3), has an E configuration; the six-membered aromatic substituent (r.m.s. deviation = 0.012 Å) is nearly coplanar with five-membered pyrazole substituent (r.m.s. deviation = 0.031 Å), the dihedral angle between the two systems being 11.4 (1)°]. The phenyl ring connected to the pyrazole ring is aligned at 45.5 (1)° with respect to this five-membered ring. The N atoms in the ring show pyramidal coordinations.

trans-3-(3,4-Dimeth-oxy-phen-yl)-2-(4-nitro-phen-yl)prop-2-ene-nitrile.

The asymmetric unit of the title compound, C(17)H(14)N(2)O(4), contains two independent mol-ecules in which the benzene rings are in a trans arrangement with respect to the C=C double bond and the rings are inclined by 4.3 (1) and 22.1 (1)° with respect to each other.

4-{[4-(Dimethylamino)benzylidene]-amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

The azomethine double-bond in the title Schiff base, C(20)H(22)N(4)O, has an E-configuration. The aromatic ring of the benzyl-idene portion (r.m.s. deviation 0.011 Å) and the five-membered pyrazolyl ring (r.m.s. deviation 0.033 Å) form a dihedral angle of 19.0 (1)°. The phenyl substituent is twisted by 55.0 (1)° with respect to the five-membered ring.

4-Nitroaniline-2,4,6-trimethoxybenz-aldehyde (1/1).

In the title co-crystal, C(6)H(6)N(2)O(2.)C(10)H(12)O(4), the two components are held together by an N-H⋯O(aldehyde) hydrogen bond. Adjacent co-crystals are linked by weaker N-H⋯O(nitro) hydrogen bonds, forming a linear chain. The two aromatic rings of the components are aligned at 75.2 (1)°. The crystal studied was a non-merohedral twin with a 24% minor component.

(2E)-1-(6-Chloro-2-methyl-4-phenyl-quinolin-3-yl)-3-phenyl-prop-2-en-1-one.

In the title compound, C(25)H(18)ClNO, the conformation about the C=C double bond is E. Significant twists are evident in the mol-ecule, with the benzene ring forming a dihedral angle of 53.92 (11)° with the quinolinyl residue. Further, the chalcone residue is approximately perpendicular to the quinolinyl residue [C(q)-C(q)-C(c)-O(c) torsion angle = -104.5 (3)°, where q = quinolinyl and c = chalcone]. In the crystal, the presence of C-H⋯O and C-H⋯π inter-actions leads to supra-molecular layers lying parallel to (02).