Heteroaryl substituted ansa‐titanocene anti‐cancer drugs derived from fulvenes and titanium dichloride

Starting from 2‐furylfulvene (1a) , 2‐thiophenylfulvene (1b) , and 1‐methyl‐2‐pyrrolylfulvene (1c), [1,2‐di(cyclopentadienyl)‐1,2‐di‐(2‐furyl)ethanediyl] titanium dichloride (2a) , [1,2‐di(cyclopentadienyl)‐1,2‐di‐(2‐thiophenyl)ethanediyl] titanium dichloride (2b) , and [1,2‐di(cyclopentadienyl)‐1,2‐bis‐(1‐methyl‐2‐pyrrolyl)ethanediyl] titanium dichloride (2c) were synthesized. When titanocenes (2a–c) were tested against pig kidney carcinoma cells (LLC‐PK), inhibitory concentrations (50%) of 4.5 × 10^?4 M , 2.9 × 10^?4 M and 2.0 × 10^?4 M respectively were observed. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and cytotoxicity studies of novel anion‐exchanged Titanocene Y derivatives

Starting from the potential anticancer drug candidate Titanocene Y {bis‐[(4‐methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride}, anion exchange experiments were performed using silver malonate (1a) or silver cyclobutane‐1,1‐malonate (1b) in order to yield bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) malonate (2a) and bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) cyclobutane‐1,1‐malonate (2b). In addition, Titanocene Y was reacted with salicylic acid (3a) or 3,5‐dinitro‐salicylic acid (3b) in the presence of diethylamine to synthesize bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) salicylate (4a) or bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) 3,5‐dinitro‐salicylate (4b). These titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC‐PK (pig kidney epithelial) cell line in an MTT‐based assay in order to determine their IC50 values. Titanocenes 2a–b and 4a were found to have IC50 values of 74 ( ± 13) µM , 18 ( ± 5) µM and 49 ( ± 11) µM on the LLC‐PK cell line, while compound 4b was found to have lost all its cytotoxic activity on this cell line. Copyright © 2010 John Wiley & Sons, Ltd.     

The preparation of a substituted titanocene-supported polymer and its application in catalytic reactions

A series of polymer-supported RCpCpTiCl₂ (Cp = η⁵  C₅H₅; RCp=η⁵  RC₅H₄) has been prepared and reduced by i-C₃H₇MgBr in situ, then used as catalysts in hydrogenation of styrene, isomerization of 1,5-cyclooctadiene and 1,5-hexadiene, and reduction of carbonyl compounds. In some cases, the introduction of a polymer ligand on the Cp ring restricts the aggregation of active sites and the formation of the inactive dimer of the titanocene species, and results in an increase of activity. Regeneration of polymer-supported titanocene catalysts was performed and the results are presented and briefly discussed.     

Synthesis and characterization of norbornene–ethylene–styrene terpolymers with a substituted ansa‐fluorenylamidodimethyltitanium‐based catalyst

This article reports a synthetic method for a norbornene–ethylene–styrene (N‐E‐S) terpolymer, which has not been well investigated so far, via incorporation of styrene (S) into vinyl‐type norbornene–ethylene (N‐E) copolymers catalyzed by a substituted ansa‐fluorenylamidodimethyltitanium [Me₂Si(3,6‐tBu₂Flu)(tBuN)]TiMe₂ catalyst ( I ) activated with a [Ph₃C][B(C₆F₅)₄]/Al(iBu)₃ cocatalyst at room temperature in toluene. The resulting terpolymerization product contained the targeted N‐E‐S terpolymer and the contaminated homopolymers, which were then able to be completely removed by solvent fractionation techniques. While homopolystyrene was easily extracted by fractionation with methylethylketone as a soluble part, homopolyethylene and a trace amount of homopolynorbornene could be perfectly separated by fractionation with chloroform as insoluble parts. The detail characterizations of a chloroform‐soluble polymer with gel permeation chromatography, nuclear magnetic resonance, and differential scanning calorimetry analyses proved that it contained a true N‐E‐S terpolymer with long N‐E sequences incorporated with isolated or short styrene sequences. The homogeneity of the morphology together with a single glass transition temperature that proportionally decreased with the increase of the styrene contents indicated that the N‐E‐S terpolymer obtained in this work is a random polymer with an amorphous structure. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2765–2773, 2007     

Organotin mefenamic complexes—preparations,spectroscopic studies and crystal structure of a triphenyltin ester of mefenamic acid: novel anti‐tuberculosis agents

The triphenyltin adduct of mefenamic acid, [SnPh₃L] ( 1 ), the monophenyltin complex [PhSnOL] _n ( 2 ), and the dibutyltin complex [SnBu₂L₂] (3), where HL is 2‐[bis(2,3‐dimethylphenyl)amino]benzoic acid (mefenamic acid), have been prepared and structurally characterized by means of vibrational, ¹H and ¹³C NMR spectroscopies. The crystal structure of 1 has been determined by X‐ray crystallography. X‐ray analysis revealed a pseudo‐pentacoordinated structure containing Ph₃Sn coordinated to the carboxylato group. The structural distortion is a displacement from the tetrahedron toward the trigonal bipyramid. Significant C? H–π interactions and intramolecular hydrogen bonds stabilize the structure 1. The polar imino hydrogen atom participates in intramolecular hydrogen bonds. Complex 1 is self‐assembled via C? H–π and stacking interactions. Vibrational and NMR data are discussed in terms of the crystal structure and the proposed structures for 1–3. Compounds 1 and 3 were tested for antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Copyright © 2002 John Wiley & Sons, Ltd.     

The synthesis and biological evaluation of a series of novel 2-COOC_2H_5/COONa substituted 1,5-benzothiazepine derivatives as antimicrobial agents

A series of novel 1,5-benzothiazepine derivatives containing COOC2H5/COONa groups at the C(2)-position were synthesized and evaluated for their antifungal and antibacterial activities by both disc diffusion and minimal inhibition concentration (MIC) methods. Most of the compounds have been shown to have moderate to good antibacterial activity against S. aureus, S. epidermidis and excellent antifungal activity against C. albicans.     

Design,synthesis and biological evaluation of substituted 2-amino-1,3-thiazine derivatives as antituberculosis and anti-cancer agents

A series of substituted 2-amino-1,3-thiazines were synthesized as amides (9a–9i), carbamates (9j–9m), sulfonamides (9n–9o) and urea derivatives (9p–9q) by treating the compound 7 with acid chlorides (8a–8i), chloroformates (8j–8m), sulfonyl chlorides (8n–8o) and isocyanates (8p–8q) respectively. The synthesized compounds (9a–9q) were screened for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv ATCC 27294 and the results show that some of these derivatives possess good activity against Mycobacterium tuberculosis H₃₇Rv ATCC 27294. A few also display promising cytotoxic activity against human breast cancer MCF-7 and human esophageal cancer EC-9706 cell lines. Regarding both biological profiles 9b, 9m and 9h are the most active for anti-cancer, anti-TB activity.     

Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist

Being obese has various health problems that are related to type 2 diabetes mellitus, cardiovascular disease, hypertension, hyperlipidemia, and fibrinolytic abnormalities. Merck's taranabant (MK-0364), a CB1R inverse agonist, is currently in Phase 3 clinical trials, and is being actively pursued by Merck toward obesity market. Merck intends to file for FDA approval of taranabant in 2008. In order to increase solubility and potency of taranabant, or even possibly improve safety, novel triazole analogues of taranabant have been designed and synthesized. We introduced a pivotal asymmetric center via the Evans chiral auxiliary methodology and set up 1,2,4-triazole via substitution of α-bromoketone. Subsequently, diastereoselective reduction was accomplished to install adjacent essential asymmetric center. This method allowed us to prepare readily sub-gram scale of the target compounds in a convenient way. The synthesized analogues were subjected to biological evaluation involving cannabinoid CB1 receptor binding affinity. While the parent taranabant bears highly potent binding affinity to cannabinoid CB1 receptor, neither of the analog structures improved CB1 receptor binding affinities.     

Anti‐cancer potential of selenium‐ and tellurium‐containing species: opportunities abound!

An overview highlighting the anti‐cancer potential of (bio‐essential) selenium‐ and tellurium‐containing species, with an emphasis on biological targets and mechanisms of action, is presented. Studies thus far have focused on selenium(II) compounds (along with – to a lesser extent – inorganic selenium and selenium nanoparticles) which often successfully exploit the inherent anti‐oxidizing ability of selenium. Significantly less work has been conducted in developing anti‐cancer tellurium compounds, yet two tellurium(IV) species are proven, clinically, as anti‐cancer agents. Given the prevalence of the disease and the accumulated insights into mechanisms of action, the continued development of selenium‐ and tellurium‐containing molecules is an area deserving greater attention. Copyright © 2012 John Wiley & Sons, Ltd.     

Development of a UPLC‐MS/MS method for routine therapeutic drug monitoring of aripiprazole,amisulpride, olanzapine,paliperidone and ziprasidone with a discussion of their therapeutic reference ranges for Chinese patients

A highly feasible and reliable ultra‐high performance liquid chromatography tandem mass spectrometry method was presented for therapeutic drug monitoring of five anti‐schizophrenic drugs (amisulpride, olanzapine, aripiprazole, paliperidone and ziprasidone) simultaneously. To meet the requirements of practical clinical usage (easy handling, high throughput and cost effectiveness), the pretreatment process was simplified (only including protein precipitation and mobile phase dilution steps) and the UPLC separation cycle was set within 6 min. The whole methodology was carefully validated according to the latest international guidelines showing the excellent selectivity, accuracy, precision, applicability and stability. After a 10 month clinical application, a retrospective analysis of 253 positive samples was carried out to investigate conformance with the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie therapeutic reference range for Chinese patients. The results suggested good consistency for olanzapine, aripiprazole, paliperidone and ziprasidone, while for amisulpride, the plasma concentration level (445.2 ± 231.5 ng/mL) was relatively higher than the recommended range (100–320 ng/mL). We supposed that such phenomenon indicated the necessity of reconstructing a Chinese‐specific therapeutic reference range for amisulpride treatment, which would be helpful to improve medication efficiency and safety for Chinese patients.     

Chemoselective synthesis and cytotoxic activity of a series of novel benzo[1,4]oxazin-3-one derivatives

That tetraacetonitrile copper perchlorate catalyzes intramolecular amidation of arenes was found to be a new strategy for construction of nitrogen-containing heterocycles and resulted in the formation of a series of novel benzo[1,4]oxazin-3-one derivatives from N-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)-2-phenoxyacetamides.This approach of heterocyclic construction proceeds in a chemoselective manner in which only benzo[1,4]oxazin-3-one derivatives were obtained by C—N bonds formation with cheap and simple copper salt catalyst under mild conditions in moderate to good yields.The biological assay of some of benzo[1,4]oxazin-3-one derivatives showed that they had moderate antiproliferative activity toward MDA-MB231 and HeLa cancer cell lines.     

The synthesis and fluorescence of a methoxy-phenyl substituted C_60-pyrrolidine derivative

A new 4-methoxyphenyl substituted C60-pyrrolidine derivative, C60(C10H13NO) (1), was prepared and its room-temperature fluorescence was studied. Its fluorescence intensity is three times stronger than that of C60. Its singlet energy was estimated to be 25 kJ/mol lower than that of C60. The fluorescence lifetime was determined to be 2.1+0.3 ns by using the frequency domain method. The fluorescence quenching by concentration and aromatic electron donor: N, N-dimethyl aniline (DMA) was investigated. Data show that its fluorescence could not be quenched by DMA.     

The Self‐Assembly of Anticancer Camptothecin–Dipeptide Nanotubes: A Minimalistic and High Drug Loading Approach to Increased Efficacy

20‐(S)‐Camptothecin (CPT)‐conjugated dipeptides are reported that preassemble into nanotubes with diameters ranging from 80–120 nm. These nanoassemblies maintain a high (～47 %) drug loading and exhibit greater drug stability (i.e., resistance to lactone hydrolysis), and consequently greater efficacy against several human cancer cells (HT‐29, A549, H460, and H23) in vitro compared with the clinically used prodrug irinotecan. A key and defining feature of this system is the use of the CPT‐conjugated dipeptide as both the drug and precursor to the nanostructured carrier, which simplifies the overall fabrication process.     

Determination of enantiomeric purity of a novel COX-2 anti-inflammatory drug by capillary electrophoresis using single and dual cyclodextrin systems

E-6087 is the most advanced compound among the cyclooxygenase-2 (COX-2) inhibitor drugs developed in our company. Its activity is mainly associated with the S(-)-enantiomer (E-6232), whereas the R(-)-enantiomer (E-6231) becomes an impurity whose content should be determined. Five main impurities and degradation products of E-6232 have been found (E-6144, E-6024, E-6072, E-6397 and E-6132), and some of them co-elute with the distomer when using a chiral high-performance liquid chromatography (HPLC) method. Consequently, we have optimized the separation of all the impurities from the two enantiomers of E-6087 by capillary electrophoresis (CE), in order to use the method for the enantiomeric purity determination of E-6232. The effect of the methanol (MeOH) content in the background electrolyte (BGE), the sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) and heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CD) concentration, and the capillary temperature have been studied. Separation of all compounds could be achieved in different systems, either in a single CD-system (with SBE-beta-CD) or in a dual CD-system (with DM-beta-CD as a neutral CD). By using the dual CD system a limit of detection (LOD) and a limit of quantitation (LOQ) of 0.03% and 0.1% of distomer, respectively, were achieved*.     

Design, synthesis and in vitro evaluation of a series thiazolidinediones analogs as PPAR modulators

A series of thiazolidinediones analogs,as PPAR modulators,were designed,synthesized and evaluated in vitro.     

Synthesis,characterization, and evaluation of biological activities of new 4′‐substituted ruthenium (II) terpyridine complexes: Prospective anti‐inflammatory properties

The synthesis and characterization of Ru (II) terpyridine complexes derived from 4′ functionalized 2,2′:6′,2″‐terpyridine (tpy) ligands are reported. The heteroleptic complexes comprise the synthesized ligands 4′‐(2‐thienyl)‐ 2,2′:6′,2″‐terpyridine) or (4′‐(3,4‐dimethoxyphenyl)‐2,2′:6′,2″‐terpyridine and (dimethyl 5‐(pyrimidin‐5‐yl)isophthalate). The new complexes [Ru(4′‐(2‐thienyl)‐2,2′:6′,2″‐terpyridine)(5‐(pyrimidin‐5‐yl)‐isophthalic acid)Cl₂] ( 9 ), [Ru(4′‐(3,4‐dimethoxyphenyl)‐2,2′:6′,2″‐terpyridine)(5‐(pyrimidin‐5‐yl)‐isophthalic acid)Cl₂] ( 10 ), and [Ru(4′‐(2‐thienyl)‐2,2′:6′,2″‐terpyridine)(5‐(pyrimidin‐5‐yl)‐isophthalic acid)(NCS)₂] ( 11 ) were characterized by ¹H‐ and ¹³C‐NMR spectroscopy, C, H, N, and S elemental analysis, UPLC‐ESI‐MS, TGA, FT‐IR, and UV‐Vis spectroscopy. The biological activities of the synthesized ligands and their Ru (II) complexes as anti‐inflammatory, antimicrobial, and anticancer agents were evaluated. Furthermore, the toxicity of the synthesized compounds was studied and compared with the standard drugs, namely, diclofenac potassium and ibuprofen, using hemolysis assay. The results indicated that the ligands and the complex 9 possess superior anti‐inflammatory activities inhibiting albumin denaturation (89.88–100%) compared with the standard drugs (51.5–88.37%) at a concentration of 500 μg g^?1. These activities were related to the presence of the chelating N‐atoms in the ligands and the exchangeable chloro‐ groups in the complex. Moreover, the chloro‐ and thiophene groups in complex 9 produce a higher anticancer activity compared with its isothiocyanate derivative in the complex 11 and the 3,4‐dimethoxyphenyl moiety in complex 10 . Considering the toxicity results, the synthesized ligands are nontoxic or far less toxic compared with the standard drugs and the metal complexes. Therefore, these newly synthesized compounds are promising anti‐inflammatory agents in addition to their moderate unique broad antimicrobial activity.     

The synthesis,structural characterization and biological evaluation of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives as potential anticancer agents

A series of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i and 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i have been synthesized by coupling ferrocenylmethyl amine 3 with various substituted N‐(fluorobenzoyl) amino acid derivatives using the standard N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride, 1‐hydroxybenzotriazole protocol. The amino acids employed in this study were glycine and L‐alanine. All of the compounds were fully characterized using a combination of ¹H NMR, ¹³C NMR, ¹⁹F NMR, distortionless enhancement by polarization transfer (DEPT)‐135, ¹H–¹H correlation spectroscopy (COSY) and ¹H–¹³C COSY (heteronuclear multiple‐quantum correlation) spectroscopy. The compounds were biologically evaluated on the oestrogen‐positive MCF‐7 breast cancer cell line. Compounds 4g , 4i , 5h and 5i exhibited cytotoxic effects on the MCF‐7 breast cancer cell line. N‐(Ferrocenylmethyl‐L‐alanine)‐3,4,5‐trifluorobenzene‐carboxamide ( 5h ) was the most active compound, with an IC₅₀ value of 2.84 μm . Compounds 4i , 5h and 5i had lower IC₅₀ values than that found for the clinically employed anticancer drug cisplatin (IC₅₀ = 16.3 μm against MCF‐7). Guanine oxidation studies confirmed that 5h was capable of generating oxidative damage via a reactive oxygen species‐mediated mechanism. Copyright © 2013 John Wiley & Sons, Ltd.     

Polyaniline doped by a new class of dopants,benzoic acid and substituted benzoic acid: synthesis and characterization

This work reports on a new class of dopants, benzoic acid and substituted benzoic acids such as 2‐hydroxybenzoic acid, 2‐chlorobenzoic acid, 4‐nitrobenzoic acid, 2‐methoxybenzoic acid, 3‐methylbenzoic acid, 4‐methylbenzoic acid, 3‐aminobenzoic acid and 4‐aminobenzoic acid, for polyaniline. Benzoic acids can be used to dope polyaniline by mixing benzoic acid (or a substituted benzoic acid) with polyaniline in the common solvent 1‐methyl‐2‐pyrrolidone. Properties of benzoic acid doped polyaniline salts are studied using Fourier transform infra‐red, X‐ray diffraction spectroscopy, scanning electron microscopy, thermogravimetric analysis and conductivity measurements. The conductivity of polyaniline‐benzoic acid salt was found to be high (10⁻² S/cm) when compared to polyaniline‐substituted benzoic acid salts (10⁻³–10⁻⁵ S/cm). Copyright © 2005 John Wiley & Sons, Ltd.