Tyrosinase inhibitory study of flavonolignans from the seeds of Silybum marianum (Milk thistle)

Anti-melanogenesis effects of silymarin from milk thistle have been reported recently, but detailed tyrosinase inhibition properties of individual components have not been investigated. This study purported to substantiate tyrosinase inhibition and its mechanism based on a single metabolite. The responsible components for tyrosinase inhibition of target source were found out as flavonolignans which consist of isosilybin A (1), isosilybin B (2), silydianin (3), 2,3-dihydrosilychristin (4), silychristin A (5), silychristin B (6) and silybin (7), respectively. The isolated flavonolignans (1–7) inhibited both monophenolase (IC₅₀ = 1.7–7.6 µM) and diphenolase (IC₅₀ = 12.1–44.9 µM) of tyrosinase significantly. Their inhibitions were 10-fold effective in comparison with their mother skeletons (8–10). Inhibitory functions were also proved by HPLC analysis using N-acetyl-l-tyrosine as substrate. The predominant formation of E_met·I was confirmed from a long prolongation of lag time and a decrease of the static state activity of the enzyme. All tested compounds had a significant binding affinity to tyrosinase with K_SV values of 0.06–0.27 × 10⁴ L·mol⁻¹, which are well correlated with IC₅₀s. In kinetic study, all flavonolignan (1–7) were mixed type I (K_I < K_IS) inhibitors, whereas their mother skeletons (8–10) were competitive ones. The UPLC-ESI-TOF/MS analysis showed that the isolated inhibitors are the most abundant metabolites in the target plant.     

Structural correlations between trans- and cis-bis(diphenylphosphino)ethene,bis(diphenylphosphino)methane and their chlorogold(I) complexes

The crystal structures of trans- and cis-bis(diphenylphosphino) ethene (1, 2) have been determined by single crystal X-ray diffraction. The conformation of these free ligands is compared with structural data available in the literature for the corresponding 1:2 complexes with gold(I) chloride (4, 5). In the cis-ligand 2 the conformation of the Ph₂P-groups is such, that the molecule approaches non-crystallographic C_s symmetry with the lone pairs at phosphorus pointing towards each other. Upon addition of AuCl, rotation of one Ph₂P group around the PC bond by approximately 60° leads to a structure for 5 which allows an intramolecular Au···Au contact of 3.05(1)Å. The trans-ligand 1 undergoes little structural change upon adduct formation, but intermolecular Au···Au contacts of 3.043(1) Å are secured through aggregation. The synthesis, properties and ¹⁹⁷Au Mössbauer spectra of 1:1 and 1:2 complexes of 1 and 2 with AuCl are summarized with reference to a recent controversy in the literature.The crystal structure of bis(diphenylphosphino)- methane (3) has also been determined and the results compared with those published previously for the 1:2 complex with AuCl (7, crystallographic C₂ symmetry, Au···Au distance 3.351(2) Å). There is very little change of the ligand conformation upon coordination.     

Synthesis and characterization of thiolato-bridged cadmium(II) complexes with NNS-chelating thiolic ligands

Cadmium(II) complexes with 2-[(2-aminoethyl)amino]ethanethiol (HL¹), 2-[(3-aminopropyl)amino]ethanethiol (HL²), 2-[(2-pyridylmethyl)amino]ethanethiol (HL³), and 2-[[2-(2-pyridyl)ethyl]amino]ethanethiol (HL⁴), [Cd(L¹)](ClO₄) (1), [Cd(L²)](ClO₄)·1/2CH₃OH (2), [Cd{Cd(L²)₂}₂](ClO₄)₂·CH₃CON(CH₃)₂ (3a·CH₃CON(CH₃)₂), [Cd{Cd(L²)₂}₂]Cl₂·2CH₃OH (3b·2CH₃OH), [Cd{Cd(L³)₂}₂](ClO₄)₂ (4), [Cd(L⁴)](ClO₄) (5), have been synthesized and characterized by measurements of the infrared and electronic spectra. The X-ray crystal structures show that 3a and 3b have a thiolato-bridged trinuclear core with a linear arrangement of three metal atoms.     

Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors

A series of [1,2,4]triazolo[4,3-a]pyrazine derivatives (4a–4i) were designed, synthesized and evaluated for their c-Met kinase inhibition and antitumor activity against SNU5 gastric cell line in vitro. Among these compounds, 4d was found to show the highest activity against c-Met and high selectivity against the tumor cells which are believed to be dependent on the c-Met oncogene amplification, because 4d selectively inhibited c-Met while had no effect on other 59 kinases. In vivo efficacy study on human gastric (MKN-45) and human non-small cell lung (NCI-H1993) tumor xenograft in nude mouse demonstrated that 4d·CH₃SO₃H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound 4d·CH₃SO₃H was found to have biological half-lives and plasma exposure values higher than those of JNJ-38877605, and its long-term toxicity and acute toxicity turned out to be acceptable, all of which indicates that 4d·CH₃SO₃H is a desirable drug candidate.     

Core electron binding energies of platinum and rhodium polysulfides

The X-ray photoelectron spectra for (NH₄)₃ [Rh(S₅)₃]·2H₂O and (NH₄)₂[PtS₁₇]·2H₂O are consistent with those previously reported for (NH₄)₂ [Pt(S₅)₃]·2H₂O, where different electron binding energies were observed for the structurally distinct sulfur atoms in the polysulfido ligands. The 4f binding energies for the platinum polysulfides are lower than those for platinum(IV) bonded to elements other than sulfur, and the 3d binding energies for the rhodium complex are lower than most values for rhodium(III) bonded to oxygen or nitrogen.     

Properties of brain L-glutamate decarboxylase: inhibition studies

—l -Glutamate decarboxylase purified from mouse brain was found to be highly sensitive to the sulfhydryl reagents, 5,5-dithiobis (2-nitrobenzoic acid) (DTNB) and p-chloromerburibenzoate (PCMB), which were competitive inhibitors (K_i for DTNB is 1·1 · 10^?8m ). Iodoacetamide and iodoacetic acid were less effective inhibitors than DTNB and PCMB. The mercapto acids, 3-mercaptopropionic, 2-mercaptopropionic, and 2-mercaptoacetic acids were potent competitive inhibitors with K_i values of 1·8, 53 and 300 μm , respectively. 2-Mercaptoethanol was less effective. Aminooxyacetic acid was the most potent carbonyl-trapping reagent tested inhibiting the enzyme activity completely at 1·6 μm , followed by hydroxylamine, hydrazine, semicarbazide, and d -penicillamine. Carboxylic acids with a net negative charge were strong competitive inhibitors e.g. d -glutamate (K_i 0·9 mm ), α-ketoglutarate (K_i, l·2mm ), fumarate (K_i,1·8 mm ), dl -β-hydroxyglutamate (K_i, 2·8 mm ), l -aspartate (k_i, 3·1 mm ) and glutarate (K_i, 3·5 mm ). 2-Aminophosphonobutyric and 2-aminophosphonopropionic acids, phosphonic analogs of glutamate and aspartate, respectively, had no effect at l0mm . γ-Aminobutyric acid, l -glutamine, l -γ-methylene-glutamine, and α,γ-diaminoglutaric acid, amino acids with no net negative charge at neutral pH, had no effect at 5 mm . Glutaric and α-ketoglutaric acids were the most potent inhibitors among the various dicarboxylic and α-keto-dicarboxylic acids tested (K_i, 3·5 and 1·2 mm , respectively). Compounds with one carbon less, succinic and oxalacetic acids, or with one carbon more, adipic and α-ketoadipic acids, were less inhibitory. The monovalent cations, Li⁺, Na⁺, NH₄⁺, and Cs⁺ had no effect on l -glutamate decarboxylase activity in concentrations up to 10mm . Divalent cations, on the other hand, were very potent inhibitors. Among eleven divalent cations tested, Zn²⁺ was the most potent inhibitor, inhibiting to the extent of 50 per cent at 10μm . The decreasing order of inhibitory potency was: Zn²⁺ > Cd²⁺, Hg²⁺, Cu²⁺ > Ni²⁺ > Mn²⁺ Co²⁺ > Ba²⁺ > Ca²⁺ > Mg²⁺ > Sr⁺², The anions, I^?, Br^?, Cl^? and F^? were only weak inhibitors. The K_i value for Cl^? was 17mm . The above findings suggest minimally the presence of aldehyde, sulfhydryl and positively charged groups at or near the active site of the holoenzyme. Intermediates of glycolysis had little effect on l -glutamate decarboxylase activity, but intermediates of the tricarboxylic acid cycle, e.g. α-ketoglutarate (K_i= 1·2 mm ) and fumarate (K_i= 1·8 mm ) were relatively potent inhibitors. The nucleotides, ATP, ADP, AMP, cyclic AMP, GTP, GDP, GMP, and cyclic GMP were weak inhibitors. l -Norepinephrine (K_i= 1·3 mm ) and serotonin were potent inhibitors, while acetylcholine, dopamine and histamine were less effective. Ethanol and dioxane inhibited the enzyme activity to the extent of 20-50 per cent at 10 per cent (v/v), while slight activation was observed at low concentrations (0·1-1 per cent) of both solvents. The possible role of Zn²⁺ and some metabolites in the regulation of steady-state levels of γ-aminobutyric acid also was discussed.     

Synthesis and cytotoxic activity of a new potential DNA bisintercalator: 1,4-Bis{3-[N-(4-chlorobenzo[g]phthalazin-1-yl)aminopropyl]}piperazine

The synthesis of new 1,4-bisalkylamino (2–4) and 1-alkylamino-4-chloro (5–6) substituted benzo[g]phthalazines is reported. Compounds 2–4 and 6 were prepared both in the free and heteroaromatic ring protonated forms. Bifunctional 6 contains the 1,4-bisaminopropylpiperazine chain as a linker between the two heteroaromatic units, whereas 5 is its monofunctional analogue. The in vitro antitumour activity of the synthesized compounds has been tested against human colon, breast and lung carcinoma cells, and also against human glioblastoma cells. Results obtained show that all of them are active in all cases, but bifunctional 6·2HCl is remarkably effective against the four cell lines tested, exhibiting IC₅₀ values in the range of 10^?7 M, similar to those found for doxorubicin. The bifunctional structure of 6·2HCl enhances activity with respect to the monofunctional related compounds 5 and 7, leading to the highest activity among all the compounds tested. Molecular modelling of 6 suggests that those results could be indicative of DNA bisintercalation, which should be specially favoured in the diprotonated form 6·2HCl, a compound suitable for being studied more in depth in further biological tests. Measure of the DNA thermal melting curves show that the linear rise in T_m for bifunctional 6·2HCl is nearly twice than that one obtained for monofunctional 5, and supports the DNA-binding hypothesis.     

Syntheses and crystal structures of trimethyltin(IV) coordination polymers based on mixed ligands of 5-nitroisophthalate and 2,2′(4,4′)-bipy or phen

The trimethyltin(IV) polymer [(Me₃Sn)₂(nip) · EtOH]_n (1) of 5-nitroisophthalic acid (H₂nip) and its three derivatives with mixed organic N-donor ligands 2,2′-bipy [(Me₃Sn)₂(nip) · 2H₂O] · [(Me₃Sn)₂(nip) · H₂O] · 2(2,2′-bipy) (2) 4,4′-bipy {[(Me₃Sn)₂(nip)]₂(4,4′-bipy)}_n (3) or phen [(Me₃Sn)₂(nip) · H₂O] · (phen) (4) have been synthesized by the reaction of trimethyltin(IV) chloride and H₂nip when sodium ethoxide was added in the presence of 2,2′-bipy 4,4′-bipy or phen. All complexes 1–4 were characterized by elemental, IR, ¹H, ¹³C, and ¹¹⁹Sn NMR spectroscopy and X-ray crystallography analyses. Crystal, data collection and structure refinement parameters for complexes 1, 2, 3 and 4 are shown in Table 1, Table 2, respectively. The X-ray data showed the geometries of all the tin atoms in complexes 1–4 are trigonal bipyramidal. The X-ray analysis of 1 showed that the structure was a polymeric infinite chain with neighboring triorganotin centers being linked by dicarboxylate ligands and hydrogen bonds were found between adjacent chains. For 2, two different monomers were found, in one monomer, Me₃Sn were coordinated to both carboxyl groups of the ligand and water molecules were coordinated to the two Sn(IV) centers. In the other monomer, water molecules were coordinated to only one Sn center. Co-crystallized2,2′-bipy was found in 2 and a 2D supermolecular structure was formed via O–H⋯O and O–H⋯N (N atoms derived from 2,2′-bipy) hydrogen bonds. In 3 however, a 2D polymeric block was formed due to the inversion center of the 4,4′-bipy. For 4, due to the O–H⋯O and O–H⋯N (N atoms derived from phen) hydrogen bonds and intermolecular Sn⋯O bonds, a 2D polymeric structure was formed.     

Expanding the 4,4′-bipyridine ligand: Structural variation in {M(pytpy)2}2+ complexes (pytpy = 4′-(4-pyridyl)-2,2′:6′,2″-terpyridine,M = Fe,Ni, Ru) and assembly of the hydrogen-bonded,one-dimensional polymer {[Ru(pytpy)(Hpytpy)]}n3n+

The solid state structures of [Ni(1)₂][NO₃]₂ · 2MeOH · 2H₂O, [Fe(1)₂][ClO₄]₂ · 2MeOH · 0.5H₂O, [Ru(1)₂][PF₆]₂ and [Ru(1)₂][PF₆][NO₃] (1 = 4′-(4-pyridyl)-2,2′:6′,2″-terpyridine) are presented and the structural variation observed for the {M(1)₂}²⁺ unit is discussed. Protonation of the pendant pyridine group in [Ru(1)₂]²⁺ leads to the formation of a hydrogen-bonded, one-dimensional polymer [{Ru(1)(H1)}_n]³ⁿ⁺ exemplifed by the solid-state structure of [{Ru(1)(H1)}{Fe(NCS)₆} · 1.25H₂O]_n.     

Synthesis,structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases

A series of new cobalt(III) complexes were prepared. They are [CoL¹(py)₃]·NO₃ (1), [CoL²(bipy)(N₃)]·CH₃OH (2), [CoL³(HL³)(N₃)]·NO₃ (3), and [CoL⁴(MeOH)(N₃)] (4), where L¹, L², L³ and L⁴ are the deprotonated form of N′-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N′-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N′-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2′-bipyridine. The complexes were characterized by infrared and UV–Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC₅₀ values of 4.27 and 0.35 μmol L⁻¹, respectively. Complex 2 has medium activity against urease, with IC₅₀ value of 68.7 μmol L⁻¹. While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed.     

Synthesis and biological evaluation of purine-pyrazole hybrids incorporating thiazole,thiazolidinone or rhodanine moiety as 15-LOX inhibitors endowed with anticancer and antioxidant potential

Novel purine-pyrazole hybrids combining thiazoles, thiazolidinones and rhodanines, were designed and tested as 15-LOX inhibitors, potential anticancer and antioxidant agents. All tested compounds were found to be potent 15-LOX inhibitors with IC₅₀ ranging from 1.76 to 6.12 µM. The prepared compounds were evaluated in vitro against five cancer cell lines: A549 (lung), Caco-2 (colon), PC3 (prostate), MCF-7 (breast) and HepG-2 (liver). Compounds 7b and 8b displayed broad spectrum anticancer activity against the five tested cell lines (IC₅₀ = 18.5–95.39 µM). While, compound 7h demonstrated moderate anticancer activity against lung A549 and colon Caco-2 cell lines. Antioxidant screening revealed that six compounds (5a, 5b, 6b, 7b, 7h and 8b) with IC₅₀ ranging from 0.93 to 14.43 µg/ml were found to be more potent scavengers of 2,2- diphenyl-1-picrylhydrazyl (DPPH) than the reference ascorbic acid with IC₅₀ value of 15.34 µg/ml. Compounds 7b, 7h and 8b, when evaluated for their antioxidant activity, where found to be potent DPPH scavengers. Moreover, compound 7b displayed twice the potency of ascorbic acid as NO scavenger. Docking study was performed to elucidate the possible binding mode of the most active compounds with the active site of 15-LOX enzyme. Collectively, the purine-pyrazole hybrids having thiazoline or thizolidinone moieties (7b, 7h and 8b) constitute a promising scaffold in designing more potent 15-LOX inhibitors with anticancer and antioxidant potential.     

Synthesis and structures of porphyrin complexes of scandium: ClSc(TTP)·2(C 10H 7Cl) and O[Sc(TTP)] 2·6THF

A facile, high yield metallation procedure is reported for the insertion of Sc into H ₂(TTP) (TTP= dianion of meso-tetratolylporphyrin) using anhydrous ScCl ₃. Single crystal X-ray structures are reported for ClSc(TPP)·2(C ₁₀H ₇Cl) ( 1) and O[Sc(TTP)] ₂·6THF ( 2). Compound 1: space group P2 ₁/c with a = 19.850(17), b = 28.822(24), c = 9.954(9)Å, β = 95.71(7)°, Z = 4; 2: space group P2/n, a = 16.952(9), b = 16.737(5), c = 19.93(1)Å, β = 112.56(5)°, Z = 4. Compounds 1 and 2 both had large amounts of poorly ordered solvents in the lattice which resulted in rather high R factors in the range of 12–14%. In 1, the Sc is five-coordinate (4N and 1Cl) and is centered 0.68Åabove the plane defined by the four porphyrin nitrogens. For 2, the Sc is 0.82Åfrom the plane and contains a non-linear μ-oxide bridge with a ScO Sc angle of 109(3)°, but with essentially coplanar porphyrin rings.     

Acetato complexes of molybdenum(V): A novel tetranuclear core based on the metal–metal bonded {Mo2O4}2+ units

A series of acetato complexes of molybdenum(V), based on the singly metal–metal bonded {Mo₂O₄}²⁺ structural fragment, has been prepared. A dinuclear (PyH)₃[Mo₂O₄Cl₄(OOCCH₃)] · CH₃CN (1) (PyH⁺ = pyridinium cation, C₅H₅NH⁺) was obtained upon the reaction of (PyH)₅[MoOCl₄(H₂O)]₃Cl₂ with the equimolar solution of pyridine and acetic acid in acetonitrile at ambient conditions. The acetato ligand in 1 is coordinated to a pair of molybdenum atoms in a syn–syn bidentate bridging manner. (PyH)_n[MoOBr₄]_n afforded in an analogous synthetic procedure a tetranuclear cluster, [Mo₄O₈(OOCCH₃)₃(OH)Py₄] · 1/2CH ₃CN · 1/2H₂O (3), with a novel core which may be envisioned as the acetate- and hydroxide-assisted assembly of {Mo₂O₄}²⁺ building blocks. Its structure is presented in terms of known tetranuclear clusters which are also composed of two {Mo₂O₄}²⁺ units. The acetato ligands in 3 adopted apart from bidentate bridging binding modes also a monodentate one. Partial substitution of chlorido ligands in (PyH)₃[Mo₂O₄Cl₄(OOCCH₃)] · CH₃CN (1) with pyridine resulted in a neutral [Mo₂O₄Cl(OOCCH₃)Py₃] · PrⁱOH · Py (2) which retained the original acetate coordination. The title compounds were fully characterized by X-ray diffraction studies and infrared vibrational spectroscopy.     

Solvatomorphs of dimeric transition metal complexes based on the V4O12 cyclic anion as building block: Crystalline packing and magnetic properties

Dinuclear [{M(phen)₂}₂V₄O₁₂] · C₆H₁₂O · H₂O (M = Co^II 1, Mn^II 2, Ni^II 3 and Cu^II 4) and [{Cu(phen)₂}₂V₄O₁₂] · 3.5H₂O 5 has been prepared by biphasic and hydrothermal syntheses, respectively. All five structures exhibit the {V₄O₁₂}^4? cluster in a chair-like configuration, covalently bonded to two [M(phen)₂]²⁺ fragments, producing a super-exchange magnetic phenomenon. The magnetic study of complexes 1–5 shows that they are very weak antiferromagnetically coupled systems, with J values of ?0.14, 2; ?0.64, 3 and ?0.23, 4 cm^?1. Complexes 1 to 3 correspond to isostructural compounds in which the cyclovanadate group acts as a bidentate bridged ligand. In the copper complexes (4 and 5) the {V₄O₁₂}^4? anion presents the novel monodentate bridging mode, and therefore a more significant distortion from the chair-like configuration. The mentioned complexes, together with that reported in the literature, permit to conclude that it is quite common for a single molecular species to exist in more than one crystalline arrangement. A detailed analysis of the structures of 1–4 shows that the crystal symmetry cannot be strictly centrosymmetric, due to the presence of the cyclohexanol molecule with a single –OH group in the lattice.     

Characterisation of metal binding sites for 8-azaadenine. Formation and X-ray structural analysis of methylmercury(II) complexes

The compounds [(CH₃Hg)AAdH]NO₃ (1) and [(CH₃Hg)AAd]·4H₂O (2) have been isolated from aqueous 1:1 solutions of CH₃HgOH and 8-azaadenine (AAdH) at respective pH values of 2 and 5. Their structures have been established by X-ray structural analysis. N9 is the metal binding site in both complexes. Alteration of the metal to ligand ratio to 2:1 at a pH of 5 allows the preparation of [(CH₃Hg)₂AAd]NO₃·H₂O (3) in which the base is coordinated at both N3 and N9. The compound [(CH₃Hg)₃AAdH₋₁]NO₃ (4), in which N1, N6 and N9 function as binding sites for the CH₃Hg⁺ cation, is formed in a 3:1 solution at a pH of 6.5. X-ray structural analyses have been performed on 3 and 4. N8 takes part in weak intermolecular secondary bonds to symmetry related Hg9 atoms in all four complexes. The relevance of the structures to an understanding of the basicities of the nitrogen atoms in 8-azaadenine and their alteration upon metal coordination of N9 and N6 is discussed.     

PTP1B inhibitors from the seeds of Iris sanguinea and their insulin mimetic activities via AMPK and ACC phosphorylation

To find PTP1B inhibitors from natural products, two new compounds (1 and 2), along with nine known compounds (3–11), were isolated from a methanol-soluble extract of Iris sanguinea seeds. The structures of compounds 1 and 2 were determined based on extensive spectroscopic data analysis including UV, IR, NMR, and MS. The IC₅₀ value of compound 5 on protein tyrosine phosphatase 1B (PTP1B) inhibitory activity is 7.30 ± 0.88 µM with a little activity compared to the IC₅₀ values of the tested positive compound. Compound 5 significantly enhanced glucose uptake and activation of pACC, pAMPK and partially Erk1/2 signaling. These results suggest that compound 5 from Iris sanguinea seeds are utilized as both PTP1B inhibitors and regulators of glucose uptake. These beneficial effects could be applied to treat metabolic diseases such as diabetes and obesity.     

Syntheses of iron(III) aroyl hydrazones containing pyridoxal and salicylaldehyde. The crystal and molecular structure of two iron(III)-pyridoxal isonicotinoyl hydrazone complexes

Iron(III) complexes of three aroyl hydrazones, pyridoxal isonicotinoyl hydrazone (H₂pih), pyridoxal benzoyl hydrazone (H₂pbh), and salicylaldehyde benzoyl hydrazone (H₂sbh), were synthesized and characterized. In aqueous medium at pH 7, [Fe(pih)(Hpih)]·3H₂O is formed. In acidic methanol, a 1:1 ligand-to-metal complex is formed, [FeCl₂(H₂pih)]Cl (1), whereas in aqueous medium at low pH cis-[FeCl₂(H₂pih)(H₂O)]Cl·H₂O (2) is formed. Compounds 1 and 2 are high-spin d⁵ with μ_eff = 5.88 μ_B and 5.93 μ_B (298 K). The crystal structures of 1 and 2 show that H₂pih acts as a tridentate neutral ligand in which the phenolic and hydrazidic protons have shifted to the pyridine nitrogen atoms. The co- ordination polyhedron of 1 is ‘square’ pyramidal, whereas that of 2 is pseudo-octahedral. Compound 1 is triclinic, space group P$\text{l}$, with a = 12.704(2) Å, b = 8.655(2) Å, c = 8.820(2) Å, α = 105.42(1)°, β = 89.87(1)°, γ = 107.60(1)°, V = 888 ų, and Z = 2; 2 is monoclinic, space group P2₁/c, with a = 15.358(4) Å, b = 7.304(3) Å, c = 17.442(4) Å, β = 101.00(2)°, V = 1921 ų, and Z = 4.     

Synthesis and evaluation of copper(II) complexes with isoniazid-derived hydrazones as anticancer and antitubercular agents

In this study, the N,N,O metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (HPCIH, 1) and its derivatives 2-acetylpyridine-(HAPIH 2), 2-pyridineformamide-(HPAmIH, 3) and pyrazineformamide-(HPzAmIH, 4) were employed in the synthesis of four copper(II) complexes, [Cu(HPCIH)Cl₂]·0.4H₂O (5), [Cu(HAPIH)Cl₂]·1.25H₂O (6), [Cu(HPAmIH)Cl₂]·H₂O (7) and [Cu(HPzAmIH)Cl₂]·1.25H₂O (8). The compounds were assayed for their action toward Mycobacterium tuberculosis H37Rv ATCC 27294 strain and the human tumor cell lines OVCAR-8 (ovarian cancer), SF-295 (glioblastoma multiforme) and HCT-116 (colon adenocarcinoma). All copper(II) complexes were more effective in reducing growth of HCT-116 and SF-295 cells than the respective free hydrazones at 5 µg/mL, whereas only complex 7 was more cytotoxic toward OVCAR-8 lines than its ligand HPAmIH. 6 proved to be cytotoxic at submicromolar doses, whose IC₅₀ values (0.39–0.86 µM) are similar to those ones found for doxorubicin (0.23–0.43 µM). Complexes 5 and 6 displayed high activity against M. tuberculosis (MIC = 0.85 and 1.58 µM, respectively), as compared with isoniazid (MIC = 2.27 µM), which suggests the compounds are attractive candidates as antitubercular drugs.     

Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors

Pin1 (Protein interacting with NIMA1) is a cis–trans isomerase and promotes the amide bond rotation of phosphoSer/Thr-Pro motifs in its substrates. Inhibition of Pin1 might be a novel strategy for developing anticancer agents. Herein, a series of pyrimidine derivatives were synthesized and their Pin1 inhibitory activities were evaluated. Among them, four compounds (2a, 2f, 2h and 2l) displayed potent inhibitory activities against Pin1 with IC₅₀ values lower than 3?µM. This series of pyrimidine-based inhibitors presented time-dependent inhibition against Pin1. The structure–activity relationships on the 2-, 4- and 5-positions of the pyrimidine ring were analyzed in details, which would facilitate further exploration of new Pin1 inhibitors.     

Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening of an in-house small molecule library for anti-lung cancer therapeutics

Pyruvate dehydrogenase kinases (PDKs) are widely over-expressed in various human solid cancers, making them attractive therapeutic targets for cancer treatment. Herein, we report the identification of structurally novel PDKs inhibitors by screening of an in-house small molecule library. Biochemical assay indicated that the identified compounds 1–4 inhibited PDK1 activity with EC₅₀ values of 0.50, 1.99, 4.64, and 0.42?µM, respectively. The ITC analysis suggested that the identified compounds 1–4 were pan-isoform PDK inhibitors, which bound to and inhibited the four PDK isoforms. Moreover, 1–4 dose-dependently reduced pyruvate dehydrogenase complex phosphorylation in NCI-H1975 cell. Molecular docking suggested that the most potent compound 4 docked well in the ATP binding pocket of the four PDK isoforms, forming direct hydrogen bond interactions with the conserved amino acids Thr and Asp in ATP binding pocket of PDKs. The cell viability assay demonstrated that 4 potently blocked NCI-H1975 cell proliferation (IC₅₀?=?3.32?µM), but had little effect on human normal lung cell MRC-5 even with the tested concentration up to 40?µM. All the data demonstrated that 4 was a promising lead for the development of structurally novel PDKs inhibitor for the cancer treatment.