Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells

Complexes [Bi(2AcPh)Cl₂]·0.5H₂O (1), [Bi(2AcpClPh)Cl₂] (2), [Bi(2AcpNO₂Ph)Cl₂] (3), [Bi(2AcpOHPh)Cl₂]·2H₂O (4), [Bi(H2BzPh)Cl₃]·2H₂O (5), [Bi(H2BzpClPh)Cl₃] (6), [Bi(2BzpNO₂Ph)Cl₂]·2H₂O (7) and [Bi(H2BzpOHPh)Cl₃]·2H₂O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO₂Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO₂Ph, H2BzpOHPh).Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4).The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts.Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO₂Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC₅₀ values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.     

New pentafluorophenyl complexes with phosphine-amide ligands

A series of nickel(II) and palladium(II) complexes containing one or two pentafluorophenyl ligands and the phosphino-amides o-Ph₂PC₆H₄CONHR [R = ⁱPr (a), Ph (b)] displaying different coordination modes have been synthesised. The chelating ability of these ligands and the influence of both coligands and the metal centre in their potential hemilabile behaviour have been explored. The crystal structure of (b) has been determined and reveals N–H⋯O intermolecular hydrogen bonding. Bis-pentafluorophenyl derivatives [M(C₆F₅)₂(o-Ph₂PC₆H₄CO-NHR)] [M = Ni; R = ⁱPr (1a); R = Ph (1b); M = Pd; R = ⁱPr (2a); R = Ph (2b)] in which (a) and (b) act as rigid P, O-chelating ligands were readily prepared from the labile precursors cis-[M(C₆F₅)₂(PhCN)₂]. X-ray structures of (1a), (1b) and (2a) have been established, allowing an interesting comparative structural discussion. Dinuclear [{Pd(C₆F₅)(tht)(μ-Cl)}₂] reacted with (a) and (b) yielding the monopentafluorophenyl complexes [Pd(C₆F₅)Cl{PPh₂(C₆H₄–CONH–R)}] (R = ⁱPr (3a), Ph (3b)) that showed a P, O-chelating behaviour of the ligands, confirmed by the crystal structure determination of (3a). New cationic palladium(II) complexes in which (a) and (b) behave as P-monodentate ligands have been synthesised by reacting them with [{Pd(C₆F₅)(tht)(μ-Cl)}₂], stoichiometric Ag(O₃SCF₃) and external chelating reagents such as cod [Pd(C₆F₅)(cod){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃)(R = ⁱPr (4a), Ph (4b)) and 2,2′-bipy [Pd(C₆F₅)(bipy){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃) (R = ⁱPr (5a), Ph (5b)). When chloride abstraction in [{Pd(C₆F₅)(tht)(μ-Cl)}₂] is promoted by means of a dithioanionic salt as dimethyl dithiophospate in the presence of (a) or (b), the corresponding neutral complexes [Pd(C₆F₅){S(S)P(OMe)₂}{PPh₂(C₆H₄-CONH-R)}] (R = ⁱPr (6a), Ph (6b)) were obtained.     

Scaffold-switching: An exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates

A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a homologous imidazo[1,2-a]pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H₃₇Rv Mtb (MIC’s of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM).     

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.     

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.     

Structure-based design,synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors

To identify compounds with potent antitumor efficacy for various human cancers, we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal structural information from c-Met and VEGFR2 in complex with known inhibitors. This led to the identification of compounds 3a and 3b, which were capable of suppressing both c-Met and VEGFR2 kinase activities. Further optimization resulted in pyrazolone and pyridone derivatives, which could form intramolecular hydrogen bonds to enforce a rigid conformation, thereby producing potent inhibition. One compound of particular note was the imidazo[1,2-a]pyridine derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both c-Met and VEGFR2 enzyme activities (IC₅₀ = 1.9, 2.2 nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC₅₀ = 5.0, 1.8 nM). Compound 26 exhibited dose-dependent antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C] = 4%, po, 5 mg/kg, once-daily) and COLO205 (T/C = 13%, po, 15 mg/kg, once-daily) mouse xenograft models.     

Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists

A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-HT₆ receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-Chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC₅₀ = 29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT₆ receptor radioligand binding assay (K_i = 1.7 nM). A screening of 5-HT_2A and 5-HT_2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT₆ receptor ligands.     

Photophysical studies of hetero-bischelated complexes of rhodium(III) containing 2,2′-dipyridylamine

Four mixed-ligand complexes, cis-Rh[(bipy)(HDPA)Cl₂]Cl (1), cis-[Rh(phen)(HDPA)Cl₂]Cl (2), cis-[Rh(bipy)(DPA)Cl₂] (3), and cis-[Rh(phen)(DPA)Cl₂] (4) (where bipy = 2,2′-bipyridine, phen = 1,10-phenantroline, HDPA = 2,2′-dipyridylamine, and DPA = the deprotonated form of 2,2′-dipyridylamine) have been synthesized and characterized. In slightly acidic solution and at low temperature (77 K), both complexes 1 and 2 show a broad, symmetric and structureless red emission with microsecond lifetime identified as dd* phosphorescence. In slightly basic solution, the deprotonated complexes (3 and 4) exhibit a broad and asymmetric blue emission, showing no vibrational structure with a lifetime in the order of microseconds. Emission of complex 3 reveals a blue shift of 0.81 μm⁻¹ compared to the emission of complex 1 and that of complex 4 shows a blue shift of 0.77 μm⁻¹ with respect to complex 2. Electrochemical data have also been obtained for the four complexes in CH₃CN. There are two reduction peaks observed for both complexes 1 and 2. Each peak is followed by a one-electron reduction at the metal, with an elimination of chloride during each reduction step, which is in consistent with the dd* phosphorescence assignment for the two complexes. For complexes 3 and 4, only a one-electron reduction process occurs at the metal with an elimination of chloride. Based on the luminescence and electrochemical data, the emission of complexes 3 and 4 are assigned as πd* phosphorescence. Results from density functional theory (DFT) calculations provide theoretical evidence in support of this πd* assignments.     

Structure and catalytic activity of rhodium(I) carbene complexes in polymerization of phenylacetylene

Rh(I) carbene complexes of [RhX(bmim)(η⁴-1,5-cod)] type (bmim = 1-butyl-3-methyl imidazolium cation, X = Cl 2, Br 3, I 4), obtained in the reaction of [Rh(OMe)(η⁴-1,5-cod)]₂ (1) with [bmim]X ionic liquids, catalyzed polymerization of phenylacetylene (PA) to cis-polyphenylacetylene (PPA) in CH₂Cl₂ and in ionic liquids. The yield of PPA increased and molecular weight (M_w) decreased after addition of phosphorus ligands PPh₃ or P(OPh)₃. Complex 4 reacted with P(OPh)₃ giving cis-[RhI(bmim)(P(OPh)₃)₂] (5) complex which catalyzed oligomerization but not polymerization of PA.     

New dinuclear cobalt(II) octaaza macrocyclic complexes with high oxidation redox potentials: Their crystal structure and unusual magnetic properties

Dinuclear cobalt(II) complexes were synthesised from 1,4,8,11-tetrakis-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tmpc), [Co₂(tmpc)Cl₂][CoCl₄] (1), [Co₂(tmpc)Cl₂][PF₆]₂ (1a) and [Co₂(tmpc)(NO₃)₂][NO₃]₂ · MeOH (2) and characterised by magnetic, spectroscopic and electrochemical techniques and by single-crystal X-ray diffraction. The X-ray structures of 1 and 2 demonstrate that in both complexes the metal ion is exo-coordinated with respect to the macrocyclic ligand. In 1, the Co(II) ions are fivefold coordinated with trigonal bipyramidal geometry, while in 2 they are sixfold coordinated with a distorted octahedral geometry. The high magnetic moments obtained for these complexes are explained in terms of a spin–orbit coupling. Magnetic measurements show a deviation from the Curie–Weiss law at low temperatures. Two magnetic orderings were observed, at high temperatures an antiferromagnetic coupling was found, below 20 K a change to a weak ferromagnetic coupling was observed. Isothermal magnetic measurements at low temperature show a weak hysteresis, which was confirmed by the small coercive field found at low temperature. In addition, for the first time an explanation for the observation that these cobalt(II) compounds are very stable towards oxidation is offered in terms of the high redox potential values obtained for 1, 1a, and 2.     

Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E2 synthase-1

Selective inhibition of pro-inflammatory prostaglandin (PG)E₂ formation via microsomal PGE₂ synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC₅₀ ? 0.1 μM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC₅₀ = 0.6 μM) as well as in intact A549 cells (IC₅₀ = 2 μM), and suppressed PGE₂ pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity was significantly less pronounced. Compound 7a significantly reduced inflammatory reactions in the carrageenan-induced mouse paw edema and rat pleurisy. Together, based on the select and potent inhibition of mPGES-1 and 5-lipoxygenase, benzo[g]indol-3-carboxylates possess potential as novel anti-inflammatory drugs with a valuable pharmacological profile.     

Two new N-heterocyclic carbene silver(I) complexes with the π–π stacking interactions

The precursors bis[N-(alkyl)benzimidazoliumylmethyl]durene halide (1a: alkyl = C₂H₅, halide = Br^?; 1b: alkyl = n-C₄H₉, halide = Cl^?; durene = 1,2,4,5-tetramethylbenzene) and their two new NHC silver(I) complexes [Durene(CH₂BimyEtAgBr)₂] (2a) and [Durene(CH₂BimyⁿBuAgCl)₂] (2b) (Bimy = benzimidazol-2-ylidene) have been prepared and characterized. In the crystal structures of 2a and 2b the aromatic π–π stacking interactions are observed.     

Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC₅₀ = 6.13 μM) is significantly higher than kojic acid (IC₅₀ = 33.3 μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.     

Linkage isomerism in the metal complex hexa(thiocyanato)rhenate(IV): Synthesis and crystal structure of (NBu4)2[Re(NCS)6] and [Zn(NO3)(Me2phen)2]2[Re(NCS)5(SCN)]

The linkage isomers [Re(NCS)₆]^2? and [Re(NCS)₅(SCN)]^2? are obtained by the reaction of [ReBr₆]^2? with NCS^? in dimethylformamide. Some differences in the chemical behavior allowed their separation and structural characterization in the form of (NBu₄)₂[Re(NCS)₆] (1) and [Zn(NO₃)(Me₂phen)₂]₂[Re(NCS)₅(SCN)] (2), respectively (Bu = n-C₄H₉ and Me₂phen = 2,9-dimethyl-1,10-phenanthroline).     

The 2-D double layer structures of indium–benzenemulticarboxylate coordination polymers with green fluorescence

Two coordination polymers, [In(btc)(2,2′-bpy)(H₂O)]_n · nH₂O (1) and [In₂(btec)(2,2′-bpy)₂Cl₂]_n (2) (H₃btc = 1,3,5-benzenetricarboxylic acid, H₄btec = 1,2,4,5-benzenetetracarboxylic acid, 2,2′-bpy = 2,2′-bipyridine), have been prepared under hydrothermal conditions. Single-crystal X-ray diffraction analyses reveal that compounds 1 and 2 consist of two-dimensional double layer structures with (3, 3) grids and (4, 2) grids, respectively. The grids along two different directions in 1 are of the opposite chirality, while the interactions of double-layer sheets in 2 create a three-dimensional supramolecular network with one-dimensional tunnels. The additional green luminescences for both 1 and 2 in the solid state at low temperature imply the red shift of emission energy in the compounds, which may derive from LMCT. Their X-ray powder diffractions and thermogravimetric analyses are also discussed.     

[S2], [S3], and [N3] coordination modes of hydrotris(thioxotriazolyl)borato. Zinc, nickel, cobalt, and bismuth complexes

The ligand hydrotris(1,4-dihydro-3-methyl-4-phenyl-5-thioxo-1,2,4-triazolyl)borato (Tr^Ph,Me) was synthetized as natrium salt and the complexes [Zn(Tr^Ph,Me)₂] · 7.5H₂O · 1.5CH₃CN (2a), [Zn(Tr^Ph,Me)₂] · 8DMF (2b), [Co(Tr^Ph,Me)₂] · 8DMF (3a), [Ni(Tr^Ph,Me)₂] · H₂O · 6DMSO (4a), [Bi(Tr^Ph,Me)₂]NO₃ (5), have been isolated and structurally characterized by X-ray diffraction. In the zinc derivatives the ligand adopts different denticity and coordination modes, η² and [S₂] for 2a and η³ and [N₃] for 2b, depending on the crystallization solvent, giving rise to tetrahedral and octahedral geometry, respectively. In the octahedral cobalt and nickel complexes the ligand is η³ and [N₃] coordinated whereas in the bismuth complex the η³ and [S₃] coordination is exhibited.     

Homogeneous CO hydrogenation and transfer hydrogenation catalyzed by ruthenium(II) complexes containing optically active Ph2PCH(Ph)CH(Me)NH2 and 1,2-C5H8(PPh2)2 ligands

Combination of (1S,2S)-cyclopentanediylbis(diphenylphosphine) with [Ru(η⁴-C₈H₁₂){η³-(CH₂)₂CMe}₂] afforded the chelate complex [Ru{η³-(CH₂)₂CMe}₂{(1S,2S)-C₅H₈(PPh₂)₂}] (1), which gave (OC-6-13)-[RuCl₂{(1S,2S)-C₅H₈(PPh₂)₂}{(1S,2S)-Ph₂PCH(Ph)CH(Me)NH₂}] (2) upon reaction with methanolic HCl in acetone, followed by the addition of the β-aminophosphine in DMF. The (P ∩ N)₂-chelated complexes (OC-6-13)-[RuCl₂{(1S,2S)-Ph₂PCH(Ph)CH(Me)NH₂}₂] (3) and (OC-6-13)-[RuCl₂{(1R,2S)-Ph₂PCH(Ph)CH(Me)NH₂}₂] (4) resulted from RuCl₃ · 3H₂O and the P,N ligands under reducing conditions. The crystal structures of 3 and 4 were determined by single-crystal X-ray diffraction. Following activation by KOBu-t in isopropanol, compounds 2–4 catalyzed the enantioselective transfer hydrogenation of acetophenone with i-PrOH as the hydrogen source as well as the direct hydrogenation of the ketone by H₂ in low to moderate e.e. (up to 67%).     

Syntheses,structures and photoluminescent property of coordination complexes with 2-(1H-1,2,4-triazol-1-yl)acetic acid

Reactions of ligand 2-(1H-1,2,4-triazol-1-yl)acetic acid (HL) with varied metal salts of Cu(II), Co(II), Ni(II), Zn(II), Cd(II) and Ag(I) result in formation of six new coordination complexes, {[Cu(L)₂] · 3H₂O}_n (1), [Co(L)₂(H₂O)₂]_n (2), [Ni(L)₂(H₂O)₂]_n (3), [Zn(L)₂(H₂O)₂]_n, (4), [Cd(L)₂]_n (5) and [Ag(L)]_n (6), and their structures were determined by X-ray crystallography. Complexes 1, 2, 3 and 4 with square-planar or octahedral metal centers have similar two-dimensional (2D) network structure with (4, 4) topology, while complex 5 displays a 2D structure with (6, 3)-connected topology. Complex 6 has a three-dimensional (3D) structure, in which the Ag(I) has tetrahedral coordination geometry. Ligand L^? acts as a 2-connected rod (bridging ligand) in 1, 2, 3 and 4, and acts as 3-connected nodes in 5 and 6. The results indicate that the coordination modes of the ligand and metal centers have great influence on the structures of the complexes. In addition, the photoluminescent properties of ligand HL and complexes 4 and 5 were studied in the solid state at room temperature.     

Derivatives of schisandrin with increased inhibitory potential on prostaglandin E2 and leukotriene B4 formation in vitro

Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB₄ production the IC₅₀ values of aR-6,7-dihydro-6-(1′-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1′-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2 ± 0.3 μM and 4.5 ± 0.2 μM, respectively. aR-6,7-Dihydro-6-(1′-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC₅₀ 32.1 ± 2.5 μM) and on LTB₄ production (37.3 ± 5.5% inhibition at 50 μM).     

Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor

Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC₅₀ value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC₅₀ of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C = 8%).