Spurious High Platelet Count without PLT Flag(S) in a Patient with Severe Aplastic Anaemia.

BACKGROUND: Platelet (PLT) count is one of the most important parameters of automated hematology, as spurious PLT reports could affect medical judgement and bring significant risks. In most cases, spurious PLT will not be reported for review criteria, which will be triggered by abnormal PLT histograms and PLT flag(s). Here, we present a case of severe aplastic anemia after hematopoietic stem cell transplantation with spurious high platelet count with normal histogram and no PLT flag(s). METHODS: The electrical impedance channel (PLT-I) and the fluorescence channel (PLT-F) of Sysmex XN-series hematology analyzer was used to obtain PLT results. Then, the sample was retested by another hematology analyzer MINDRAY BC-7500 [NR] CRP, and incubation was performed to rule out cryoglobulin interference. Furthermore, a microscope was used to estimate the PLT count by the ratio of platelets to red blood cells and observe the morphology of cells. RESULTS: Both PLT-I and PLT-F test results were spuriously high, and microscopically assessed platelet counts were relatively reliable. The observed spiny cells and ghost cells caused by hemolysis may have contributed to the inaccuracy of instrumental counting in this case. CONCLUSIONS: For special hematologic patients, PLT-I with flags may not be sufficient for screening purposes and PLT-F is not always accurate. Multiple testing methods including manual microscopy are needed.

Platelet indices and angiogenesis markers in hypertensive disorders of pregnancy.

INTRODUCTION: Activated platelets exert a key role in the pathogenesis of preeclampsia (PE). There is evidence of distinctive patterns of platelet indices in PE in comparison to healthy pregnancies, therefore these indices can be potential tools for PE detection, risk stratification, and management. Considering the vascular aspects of its pathophysiology, PE is characterized by the increased levels of soluble FMS-like tyrosine kinase-1 (sFlt-1) an antiangiogenic factor, and reduced placental growth factor (PlGF), a proangiogenic factor. This study aimed to assess the platelet indices in hypertensive disorders of pregnancy (HDP) and its correlation with angiogenesis-related biomarkers. METHODS: The groups for the study were: control (n = 114); gestational hypertension; (n = 112), and PE (n = 42). The platelet indices included were platelet counts (PLT-I and PLT-F), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), and immature platelet fraction (IPF# and IPF%). Serum levels of sFlt-1 and PlGF were assessed. RESULTS: PLT-I, PLT-F, and PCT% were lower in PE, while MPV, PDW, P-LCR, IPF%, and IPF# were increased. The parameter MPV presented the best performance for the discrimination of PE. There was a moderate positive correlation between sFlt-1 levels and MPV, PDW, and P-LCR. CONCLUSION: Platelet indices can be potentially applied as additional tools for the diagnosis and management of HDP. Activated platelets may act as an extra source of sFlt-1 in PE.

Protective effect of lodoxamide on hepatic steatosis through GPR35.

Although GPR35 is an orphan G protein-coupled receptor, synthetic agonists and antagonists have been developed. Recently, cromolyn, a mast cell stabilizer, was reported as an agonist of GPR35 and was shown to exhibit antifibrotic effects through its actions on hepatocytes and stellate cells. In this study, the role of GPR35 in hepatic steatosis was investigated using an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis and an in vivo model of high fat diet-induced liver steatosis. GPR35 was expressed in Hep3B human hepatoma cells and mouse primary hepatocytes. A specific LXR activator, T0901317, induced lipid accumulation in Hep3B cells. Lodoxamide, the most potent agonist of GPR35, inhibited lipid accumulation in a concentration-dependent manner. The protective effect of lodoxamide was inhibited by a specific GPR35 antagonist, CID2745687, and by siRNA-mediated knockdown of GPR35. The expression of SREBP-1c, a key transcription factor for lipid synthesis, was induced by T0901317 and the induction was inhibited by lodoxamide. Through the use of specific inhibitors of cellular signaling components, the lodoxamide-induced inhibition of lipid accumulation was found to be mediated through p38 MAPKs and JNK, but not through Gi/o proteins and ERKs. Furthermore, the protective effect of lodoxamide was confirmed in mouse primary hepatocytes. Lodoxamide suppressed high fat diet-induced fatty liver development, which suggested the protective function of GPR35 in liver steatosis. Therefore, the present data suggest that GPR35 may function to protect against fatty liver development.

An ATP-Dependent Ligase with Substrate Flexibility Involved in Assembly of the Peptidyl Nucleoside Antibiotic Polyoxin.

Polyoxin (POL) is an unusual peptidyl nucleoside antibiotic, in which the peptidyl moiety and nucleoside skeleton are linked by an amide bond. However, their biosynthesis remains poorly understood. Here, we report the deciphering of PolG as an ATP-dependent ligase responsible for the assembly of POL. A polG mutant is capable of accumulating multiple intermediates, including the peptidyl moiety (carbamoylpolyoxamic acid [CPOAA]) and the nucleoside skeletons (POL-C and the previously overlooked thymine POL-C). We further demonstrate that PolG employs an ATP-dependent mechanism for amide bond formation and that the generation of the hybrid nucleoside antibiotic POL-N is also governed by PolG. Finally, we determined that the deduced ATP-binding sites are functionally essential for PolG and that they are highly conserved in a number of related ATP-dependent ligases. These insights have allowed us to propose a catalytic mechanism for the assembly of peptidyl nucleoside antibiotic via an acyl-phosphate intermediate and have opened the way for the combinatorial biosynthesis/pathway engineering of this group of nucleoside antibiotics.IMPORTANCE POL is well known for its remarkable antifungal bioactivities and unusual structural features. Actually, elucidation of the POL assembly logic not only provides the enzymatic basis for further biosynthetic understanding of related peptidyl nucleoside antibiotics but also contributes to the rational generation of more hybrid nucleoside antibiotics via synthetic biology strategy.

Biodegradable Oxamide-Phenylene-Based Mesoporous Organosilica Nanoparticles with Unprecedented Drug Payloads for Delivery in Cells.

We describe biodegradable mesoporous hybrid nanoparticles (NPs) in the presence of proteins and their applications for drug delivery. We synthesized oxamide phenylene-based mesoporous organosilica nanoparticles (MON) in the absence of a silica source which had remarkably high organic content and high surface areas. Oxamide functions provided biodegradability in the presence of trypsin model proteins. MON displayed exceptionally high payloads of hydrophilic and hydrophobic drugs (up to 84 wt %), and a unique zero premature leakage without the pore capping, unlike mesoporous silica. MON were biocompatible and internalized into cancer cells for drug delivery.

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.

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase.

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.

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.

Self-assembly of oxamidato bridged ester functionalised dirhenium metallastirrups: synthesis, characterisation and cytotoxicity studies.

A new set of ester functionalised Re(i)-based oxamidato bridged neutral dinuclear metallacycles were synthesised by self-assembly of four components from three building blocks in a facile one-pot reaction via an orthogonal bonding approach. Oxidative addition of oxamide ligands (H2L = N,N'-diphenyloxamide, and N,N'-dibenzyloxamide) to rhenium carbonyl (Re2(CO)10) in the presence of semi-rigid and flexible ditopic pyridyl ligands (L' = o-phenylene diisonicotinate (pdi), ethane diyl di-4-pyridine carboxylate (etdp) and 1,4-butane diyl di-4-pyridine carboxylate (budp)) having ester functionality afforded neutral dirhenium metallacycles of the general formula [(CO)3Re(µ-L)(µ-L')Re(CO)3] (1-5) under solvothermal reaction conditions. The metallacyclic compounds were characterised using elemental analyses, IR, UV-vis and NMR spectroscopic techniques. Structural analyses of 2-5 by single crystal X-ray diffraction methods revealed a stirrup like molecular framework in which two fac-Re(CO)3 units are bridged together by dissymmetrical NO∩ON bis-chelation of oxamide ligands (as a pedestal of stirrups) and further connected by a flexible ditopic tecton (as an arched anchor of stirrups) in an orthogonal fashion. The cytotoxicity activities of dirhenium metallacycles 1-5 were studied in vitro against three different cancer cell lines and normal cells.

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 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.

Effect of oxamic analogues on functional mice sperm parameters.

The present study evaluates the effect of oxamate derivatives (N-ethyl, N-propyl, N-butyl oxamates) on functional murine sperm parameters, towards a new male non-hormonal contraceptive. These derivatives are selective inhibitors of lactate dehydrogenase-C4 (LDH-C4). LDH-C4 is a sperm-specific enzyme that plays an important role in ATP production for maintaining progressive motility as well as to induce capacitation and hyperactivation. The results demonstrate that all oxamate derivatives selectively inhibited LDH-C4 in mouse sperm extracts. The IC(50) values for hexokinase and glyceraldehyde-3-phosphate dehydrogenase were at least an order of magnitude greater than LDH-C4 IC(50) values. Prodrugs of oxamate derivatives assayed on sperm cells diminished normal sperm motility parameters, acrosome reaction, and cell viability in a concentration dependent manner. Also, we performed in vivo studies to determine the potential toxicity and possible contraceptive ability of these inhibitors. Mouse sperm were more sensitive to the N-butyl oxamate ethyl ester (NBOXet). Furthermore, results showed that NBOXet was of a low toxicity substance that diminished the total and progressive motility as well as the kinematic parameters of sperm cells. Data from in vitro and in vivo studies showed that N-butyl oxamate and its prodrug, are selective inhibitors of sperm LDH-C4, has low toxicity, and inhibits sperm progressive motility, offering some of the desirable characteristics of a male contraceptive: effect, low toxicity, and selectivity.

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.

Vernal keratoconjunctivitis: a severe allergic eye disease with remodeling changes.

Vernal keratoconjunctivitis (VKC) is an unusually severe sight-threatening allergic eye disease, occurring mainly in children. Conventional therapy for allergic conjunctivitis is generally not adequate for VKC. Pediatricians and allergists are often not familiar with the severe clinical symptoms and signs of VKC. As untreated VKC can lead to permanent visual loss, pediatric allergists should be aware of the management and therapeutic options for this disease to allow patients to enter clinical remission with the least side effects and sequelae. Children with VKC present with severe ocular symptoms, that is, severe eye itching and irritation, constant tearing, red eye, eye discharge, and photophobia. On examination, giant papillae are frequently observed on the upper tarsal conjunctiva (cobblestoning appearance), with some developing gelatinous infiltrations around the limbus surrounding the cornea (Horner-Trantas dot). Conjunctival injections are mostly severe with thick mucus ropy discharge. Eosinophils are the predominant cells found in the tears and eye discharge. Common therapies include topical antihistamines and dual-acting agents, such as lodoxamide and olopatadine. These are infrequently sufficient and topical corticosteroids are often required for the treatment of flare ups. Ocular surface remodeling leads to severe suffering and complications, such as corneal ulcers/scars. Other complications include side effects from chronic topical steroids use, such as increased intraocular pressure, glaucoma, cataract and infections. Alternative therapies for VKC include immunomodulators, such as cyclosporine A and tacrolimus. Surgery is reserved for those with complications and should be handled by ophthalmologists with special expertise. Newer research on the pathogenesis of VKC is reviewed in this article. Vernal keratoconjunctivitis is a very important allergic eye disease in children. Complications and remodeling changes are unique and can lead to blindness. Understanding of pathogenesis of VKC may lead to better therapy for these unfortunate patients.

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.

Bimetallic complexes constructed from asymmetrical N,N'-bis(substituted)-oxamide: cytotoxicities, and reactivities towards DNA and protein.

A new asymmetrical N,N'-bis(substituted)oxamide ligand, N-(5-chloro-2-hydroxyphenyl)-N'-[3-(dimethylamino)propyl]oxamide (C(13)H(18)N(3)O(3)Cl·H(2)O, H(3)L) and its two binuclear complexes [Cu(2)L(H(2)O)(bpy)](ClO(4))·CH(3)OH (1) and [Ni(2)L(bpy)(2)](ClO(4)) (2) [bpy = 2,2'-bipyridine] have been synthesized and characterized by X-ray single-crystal diffraction. In the crystal structure, H(3)L adopting a transoid conformation occurs as a neutral molecule linked with a water molecule by an intermolecular hydrogen bond. In the two complexes, the cis-L(3-) ligand bridges two metal ions with the corresponding separations of 5.2032(15) Å (1) and 5.2466(7) Å (2), respectively. In vitro cytotoxic activities, and the reactivities of the three compounds towards DNA and protein are investigated.

Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation.

Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

Synthesis and structure of new bicopper(II) complexes bridged by N-(2- aminopropyl)-N'-(2-oxidophenyl)oxamide: the effects of terminal ligands on structures, anticancer activities and DNA-binding properties.

A novel dissymmetrical N,N'-bis(substituted)oxamide ligand, N-(2-aminopropyl)-N'-(2-oxido- phenyl)oxamide (H(3)apopoxd) (L), and its three bicopper(II) complexes, [Cu(2)(apopoxd)(bpy)]- (ClO(4))·H(2)O (1), [Cu(2)(apopoxd)(dabt)](ClO(4))·2H(2)O (2), and [Cu(2)(apopoxd)(phen)(2)](ClO(4)) (3) (bpy = 2,2'-bipyridine; dabt = 2,2'-diamino-4,4'-bithiazole; phen = 1,10-phenanthroline) have been synthesized and characterized. The crystal structures of the three bicopper(II) complexes have been determined by X-ray single-crystal diffraction. In complexes 1 and 2, the cis-apopoxd(3-) ligands bridge two copper(II) ions in square-planar geometries with the corresponding separations of 5.1868(3) and 5.2016(4) Å, respectively. While in complex 3, the apopoxd(3-) ligand adopting a trans conformation bridges the two copper(II) ions in distorted square-pyramid environments with a Cu · · · Cu distance of 5.2508(7) Å. The anticancer activities and DNA-binding properties of L and the three complexes were investigated.