Structural and biological investigation of ferrocene-substituted 3-methylidene-1,3-dihydro-2H-indol-2-ones

The Knoevenagel condensation of 1,3-dihydro-2H-indol-2-one with ferrocene carboxaldehyde afforded an approximate 2:1 mixture of the geometrical isomers (E)- and (Z)-3-ferrocenylmethylidene-1,3-dihydro-2H-indol-2-one respectively in an overall 67% yield; the air and solution-stable isomers were readily separated by preparative thin layer chromatography and their structures were unequivocally elucidated in solution, by (1)H NMR spectroscopy, and in the solid phase, by X-ray crystallography; both isomers of displayed in vitro toxicity against B16 melanoma and Vero cell lines in the micromolar range and inhibited the kinase VEGFR-2 with IC(50) values of ca. 200 nM.

Synthesis of a 1,4-benzodiazepine containing palladacycle with in vitro anticancer and cathepsin B activity

The reaction of the five-membered C,N-palladacycle [(L)PdCl](2), where LH = 1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one, with 1,2-ethanebis(diphenylphosphine), dppe, leads to the formation of the bridged palladacycle. [Pd(2)L(2)(mu-dppe)Cl(2)] 3, which was characterised in solution by (1)H and (31)P NMR spectroscopy and in the solid state by X-ray crystallography. Complex 3 was tested in vitro against a number of cell lines. For example, it inhibited K562 leukaemia cells with an IC(50) value of 4.3 microM (1 h exposure) and displayed cathepsin B inhibitory action with an IC(50) value of 3 microM.

Investigating the impact of aircraft exit availability on egress time using computer simulation

This paper examines the influence of exit availability on evacuation time for narrow body aircraft under certification trial conditions using computer simulation. A narrow body aircraft which has previously passed the certification trial is used as the test configuration. While maintaining the certification requirement of 50% of the available exits, six different configurations are examined. These include the standard certification and five other exit configurations based on commonly occurring exit combinations found in accidents. These configurations are based on data derived from the AASK database and the evacuation simulations are performed using the airEXODUS evacuation software. The results show that the certification practise of using half of the available exits predominately down one side of the aircraft is neither statistically relevant nor challenging. For the aircraft cabin layout examined, the exit configuration used in certification trial produces the shortest egress times. Furthermore, three of the six exit combinations investigated result in predicted egress times in excess of 90 seconds, suggesting that the aircraft would not satisfy the certification requirement under these conditions.

Synthesis and enzymatic evaluation of the guanosine analogue 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG): insights into the phosphorolysis reaction mechanism based on the blueprint transition state: SN1 or SN2?

A modified experimental procedure for the synthesis of MESG (2-amino-6-mercapto-7-methylpurine ribonucleoside) 1 has been successfully performed and its full characterization is presented. High resolution ESI(+)-MSMS indicates both the nucleoside bond cleavage as the main fragmentation in the gas phase and a possible SN1 mechanism. Ab initio transition state calculations based on the blue print transition state support this mechanistic rationale and discard an alternative SN2 mechanism. Assays using purine nucleoside phosphorylase (PNP) enzyme (human and M. tuberculosis sources) indicate its efficiency in the phosphorolysis of MESG and allow the quantitative determination of inorganic phosphate in real time assay.

Excellent correlation between cathepsin B inhibition and cytotoxicity for a series of palladacycles

The reaction of the five- or six-membered C,N or C,S-palladacycles [(L)PdCl](2) with PTA (1,3,5-triaza-7-phosphaadamantane) led to the monomeric complexes [(L)Pd(PTA)Cl] 6a, 6b and 7 where LH= N,N-dimethyl-1-phenylmethanamine, benzyl(methyl)sulfane or 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one respectively. Dimeric complexes have also been synthesised: [Pd(2)L(2)(mu-dppe)Cl(2)], where LH = 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1a), (R)- or (S)-3-isopropyl-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1b, 1c), [Pd(2)L(2)(mu-dppf)Cl(2)], where L= 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4a) or (R)-3-isopropyl-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4b), respectively, and dppe = 1,2-bis(diphenylphosphino)ethane, dppf = 1,1'-bis(diphenylphosphino)ferrocene. The complexes were characterised in solution, by (1)H and (31)P NMR spectroscopy, and single crystals of complexes 6b and 7 were studied in the solid state by X-ray crystallography. The palladacycles were evaluated for in vitro activity as cytotoxic agents on A2780/S cells and also as cathepsin B inhibitors, an enzyme implicated in a number of cancer related events.

Microwave mediated reduction of heterocycle and fluorine containing nitroaromatics with Mo(CO)(6) and DBU

Heterocycle containing nitroaromatics were reduced by Mo(CO)(6) and DBU in EtOH under microwave irradiation within 15 min. Under the same conditions, 4-fluoronitrobenzene was reduced to 4-fluoroaniline, whereas 2-chloro-1-fluoro-4-nitrobenzene afforded a mixture of 3-chloro-4-fluoroaniline and 3-chloro-4-ethoxyaniline. The extent of the competing SNAr/reduction process could be influenced by the nature of the solvent, with t-BuOH the inert solvent of choice. The latter was used as solvent for SNAr/reductions of 2-chloro-1-fluoro-4-nitrobenzene with S-nucleophiles to yield 3-chloro-4-mercaptoanilines. Crown Copyright (c) 2008 Published by Elsevier Ltd. All rights reserved.

Other uses of palladacycles in synthesis

Summary: This chapter contains sections titled: * Introduction * Chiral Palladacycles in Aldol and Related Transformations * Catalytic Allylic Rearrangements * Catalytic C-C Bond-Forming Reactions * Oxidations Involving Palladacycles * Conclusion * References

Synthesis of cycloruthenated compounds as potential anticancer agents

A library of 19 cycloruthenated derivatives is constructed by making use of the well-known cyclometalation reaction. Their geometries are modified in a straightforward manner by addition of either mono- or bidentate ligands, such as bipyridine, phenanthroline, 1,2-bis(diphenylphosphanyl)ethane, dimethylphenylphosphane, triphenylphosphane, and 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (PTA) ligands, to cationic cycloruthenated centers. The antitumor properties of the compounds thus obtained are investigated in order to compare them with recently reported ruthenium complexes and cisplatin. IC50 values against mammalian cells (A-172, HCT-116, and RDM-4) are determined for the library compounds and some of them, such as those derived from orthoruthenated phenylpyridine and a bidentate N,N ligand, display activity of the same order of magnitude as cisplatin.

Molybdenum hexacarbonyl and DBU reduction of nitro compounds under microwave irradiation

An ethanolic mixture of molybdenurn hexacarbonyl and DBU mediates the reduction of nitroarenes to the corresponding anilines in excellent yields in 15-30 minutes under microwave irradiation.

Conference report: 7th Annual Congress of International Drug Discovery Science and Technology

This is a report on the 7th Annual Congress of International Drug Discovery Science and Technology held in Shanghai, China from 22–25 October, 2009. The conference, organized by BIT Life Sciences, comprised several parallel sessions, keynote presentations and a selection of selection of 20-minute presentations covering a range of therapeutic areas, including general medicinal chemistry, oncology, inflammation, receptors and ion channels, drug, metabolism and pharmokinetics, and fragment-based drug discovery. There were also sessions devoted to genomics, biomarkers, immunology, cell biology, molecular imaging and biochips. Supported by an exhibition of services/products and posters, the conference underlined the marked presence of Asian CROs.