Transition-Metal-Free Continuous-Flow Synthesis of 2,5-Diaryl Furans: Access to Medicinal Building Blocks and Optoelectronic Materials.

The direct transformation of 1,3-dienes into valuable 2,5-diarylfurans using transition-metal-free conditions is presented. By employing a simple oxidation─dehydration sequence on readily accessible 1,3-dienes, important 2,5-diarylfuran building blocks frequently used in medicinal and material chemistry are prepared. The oxidation step is realized using singlet oxygen, and the intermediate endoperoxide is dehydrated under metal-free conditions and at ambient temperature using the Appel reagent. Notably, this sequence can be streamlined into continuous flow, thereby eliminating the isolation of the intermediate, often unstable endoperoxide. This leads to a significant improvement in isolated yields (ca. 27% average increase) of the 2,5-diarylfurans while also increasing safety and reducing waste. Our transition-metal-free synthetic approach to 2,5-diarylfurans delivers several important furan building blocks used commonly in medicinal chemistry and as optoelectronic materials, including short-chain linearly conjugated furan oligomers. Consequently, we also complete a short study of the optical and electrochemical properties of a selection of these novel materials.

Indium-Mediated 2-Oxonia Cope Rearrangement of 1,4-Dienols to 1,3-Dienols.

An indium-mediated isomerization of 1,4-dienols to 1,3-dienols is described. This procedure consists of the addition of pentadienylindium, in a protic solvent, to aldehydes giving the kinetic γ-allylation product in high yields. The subsequent conversion of this γ-allylation product to its thermodynamic 1,3-dienol α-isomer can be achieved by its exposure to indium triflate in the presence of a substoichiometric amount of aldehyde at room temperature. This transformation exhibited moderate to good substrate scope and has been shown to proceed by a 2-oxonia Cope rearrangement.

Total Synthesis of the Tetrasubstituted Furan Fatty Acid Metabolite CeDFP via Au-Catalyzed Intermolecular Alkyne Hydroarylation.

The first total synthesis of the tetrasubstituted furan fatty acid (FFA) metabolite 5-[(1 E)-2-carboxyethenyl]-3,4-dimethyl-2-furanpentanoic acid (CeDFP) is reported. CeDFP is a FFA metabolite isolated from shark livers and is related to the known FFA metabolites CMPF and CMPentylF. Key elements of the synthetic route to CeDFP include an iodine-promoted 5- endo- dig cyclization of a 1,2-alkyne diol, a methyllithium-mediated insertion of the C3-methyl group, and a Au(I)-catalyzed intermolecular hydroarylation to introduce the unsaturated ester.

Resolvin E1 (Rv E1 ) attenuates LPS induced inflammation and subsequent atrophy in C2C12 myotubes.

Resolution of inflammation is now known to be an active process which in part is instigated and controlled by specialized pro-resolving lipid mediators (SPM's) derived from dietary omega-3 fatty acids. Resolvin E1 (Rv E1 ) is one of these SPM's derived from the omega-3 fatty acid eicosapentaenoic acid. Using both molecular and phenotypic functional measures we report that in a model of Lipopolysaccharide (LPS) induced inflammation, Rv E1 attenuated mRNA levels of both interlukin-6 and monocyte chemoattractant protein-1 whilst having no effect on tumor necrosis factor-α or interlukin-1ß in C2C12 skeletal muscle myotubes. Findings at the molecular level were transferred into similar changes in extracellular protein levels of the corresponding genes with the greatest attenuation being noted in IL-6 protein concentrations. Rv E1 instigated beneficial morphological changes through the prevention of LPS induced skeletal muscle atrophy, in tandem with attenuation of the LPS induced reduction in contractile force in tissue engineered skeletal muscle. These findings demonstrate, in our model of endotoxin induced inflammation in skeletal muscle, that Rv E1 has pro-resolving properties in this cell type. Our data provides rationale for further investigation into the mechanistic action of Rv E1 in skeletal muscle, with the vision of having potential benefits for the prevention/resolution of in-vivo skeletal muscle atrophy.

A biosynthetically inspired route to substituted furans using the Appel reaction: total synthesis of the furan fatty acid F5.

Appel reaction conditions have been harnessed to affect a mild biosynthetically inspired dehydration of endoperoxides to deliver multi-substituted electron rich furans. Unlike traditional dehydrative procedures, this method is metal and acid free, and can be achieved under redox neutral conditions. It is general for a range of aryl and alkyl substituted endoperoxides, and is functional group tolerant. Furthermore, this procedure has been used to deliver an effective total synthesis of the furan fatty acid (FFA) F5.

A mild Lewis acid mediated epoxy-ester to bicyclic ortho ester rearrangement.

A high yielding rearrangement of epoxy-esters, under Lewis acid conditions, to give bicyclic ortho esters is reported.

Preparation of highly substituted tetrahydropyrans via a metal assisted dipolar cycloaddition reaction.

A range of highly substituted tetrahydropyrans have been prepared by reaction of a donor-acceptor cyclobutane, where the donor is a metal-alkyne complex, with an aldehyde under Lewis acid conditions.

Mechanistic insights into the inhibition of prostate specific antigen by beta-lactam class compounds.

Prostate Specific Antigen (PSA) is a biomarker used in the diagnosis of prostate cancer and to monitor therapeutic response. However, its precise role in prostate carcinogenesis and metastasis remains largely unknown. A number of studies arguing in the favor of an active role of PSA in prostate cancer development and progression have implicated this serine protease in the release and activation of growth factors such as insulin-like growth factor 1 (IGF1) through cleavage of insulin like growth factor binding protein 3 and Transforming Growth Factor beta (TGF-beta) through cleavage of Latent TGF-beta. In contrast, other studies suggest that PSA activity might hinder tumor development and progression. In light of these contradictory findings, efficient inhibitors of PSA are needed for exploring its biological role in tumor development and metastasis. Towards the goal of developing potent inhibitors of PSA, we have explored the molecular mechanism of a series of beta-lactam based compounds on binding to PSA using activity assays, matrix assisted laser desorption ionization with a time-of-flight mass spectrometry, and GOLD docking methodology. The mass spectrometry experiments and the activity assays confirmed the time-dependent and covalent nature of beta-lactam binding. To gain insights on the reaction intermediates at the molecular level, we docked beta-lactam inhibitors to a homology modeled PSA using the GOLD docking program in noncovalent and covalent binding modes. The docking studies elucidated the molecular details of the early noncovalent Michaelis complex, the acyl-enzyme covalent complex, and the nature of conformational reorganization required for the long term stability of the covalent complex. Additionally, the molecular basis for the effect of stereochemistry of the lactam ring on the inhibitory potency was elucidated through docking of beta-lactam enantiomers. As a validation of our docking methodology, two novel enantiomers were synthesized and evaluated for their inhibitory potency using fluorogenic substrate based activity assays. Additionally, cis enantiomers of eight beta-lactam compounds reported in a previous study were docked and their GOLD scores and binding modes were analyzed in order to assess the general applicability of our docking results. The close agreement of our docking results with the experimental data validates the mechanistic insights revealed through the docking studies and paves the way for the design and development of potent and specific inhibitors of PSA.

Novel formation and use of a Nicholas carbocation in the synthesis of highly substituted tetrahydrofurans.

The first formation of a Nicholas carbocation through cleavage of a carbon-carbon sigma bond has allowed the preparation of highly substituted tetrahydrofurans in a formal dipolar cycloaddition reaction.

An unusual oxidative cyclization: studies towards the biomimetic synthesis of pyridomacrolidin.

An unusual oxidative cyclization of a N-hydroxy pyridone 9 with Z-2-cyclodecenone 11 has been achieved, thus demonstrating a possible biomimetic route to pyridomacrolidin 2. [reaction: see text]

Biomimetic cycloaddition approach to tropolone natural products via a tropolone ortho-quinone methide.

[reaction: see text] A study toward a possible biomimetic hetero Diels-Alder reaction is reported between humulene and a novel tropolone ortho-quinone methide. A suitable tropolone ortho-quinone methide precursor has been prepared from 3-methyl-2-furoate. Heating the ortho-quinone methide precursor gave a tropolone ortho-quinone methide, which in the presence of humulene underwent a hetero Diels-Alder reaction to give a deoxy analogue of epolone B.

Total synthesis of pyridovericin: studies toward the biomimetic synthesis of pyridomacrolidin.

[reaction: see text] The total synthesis of the novel metabolite pyridovericin 1 is reported. The synthesis of this key intermediate in our proposed biomimetic synthesis of pyridomacrolidin 2 has been accomplished in good yield from readily available 2,4-dihydroxypyridine.

Prostate-specific antigen (PSA)-mediated proliferation, androgenic regulation and inhibitory effects of LY312340 in HOS-TE85 (TE85) human osteosarcoma cells.

BACKGROUND: PSA mediates growth factor responses that stimulate proliferation of prostatic and other cellular types. Androgen-sensitive TE85 human osteosarcoma cells were used to study PSA as a potential mediator of prostatic cancer growth and osseous metastasis. MATERIALS AND METHODS: TE85 cells were probed for PSA mRNA and protein levels under testosterone (T)-replete and--depleted conditions. TE85 proliferative responses to PSA were evaluated in the absence and presence of LY312340, a monocyclic beta-lactam inhibitor of PSA enzymatic activity. RESULTS: A 3.1-fold increase in PSA mRNA was observed following T stimulation. Low levels of immunoreactive PSA (iPSA) were detected in media of androgen-stimulated TE85 cells while iPSA was not found in control media. Conversely, iPSA was detected in TE85 cell pellets from control but not in androgen-stimulated cell cultures. Exogenously added enzymatically active PSA stimulated TE85 proliferation in a bi-phasic manner. LY312340 inhibited PSA-induced increases in TE85 cell numbers but had no effect on basal or T- stimulated cellular proliferation. CONCLUSION: While the PSA levels produced by TE-85 cells in response to androgen stimulation are too low to be biologically active, PSA produced by metastatic PCa cells may mediate paracrine stimulation of osteogenic PCa metastasis. Inhibitors of PSA enzymatic activity could be useful therapeutic agents.