Resatorvid‐based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV‐induced NF‐κB and AP‐1 Signaling in Keratinocytes and Mouse Skin

Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (NMSC) are urgently needed. Toll‐like receptor 4 (TLR4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous TLR4 for the suppression of UV‐induced NF‐κB and AP‐1 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of TLR4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA‐based genetic TLR4 inhibition blocks UV‐induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (TAK‐242), a molecularly targeted clinical TLR4 antagonist, blocks UV‐induced NF‐κB and MAP kinase/AP‐1 activity and cytokine expression (Il‐6, Il‐8, and Il‐10) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological TLR4 antagonism can suppress UV‐induced cutaneous signaling, and future experiments will explore the potential of TLR4‐directed strategies for prevention of NMSC.     

Three-dimensional packing structure and electronic properties of biaxially oriented poly(2,5-bis(3-alkylthiophene-2-yl)thieno[3,2-b]thiophene) films

We use a systematic approach that combines experimental X-ray diffraction (XRD) and computational modeling based on molecular mechanics and two-dimensional XRD simulations to develop a detailed model of the molecular-scale packing structure of poly(2,5-bis (3-tetradecylthiophene-2-yl)thieno[3,2-b]thiophene) (PBTTT-C(14)) films. Both uniaxially and biaxially aligned films are used in this comparison and lead to an improved understanding of the molecular-scale orientation and crystal structure. We then examine how individual polymer components (i.e., conjugated backbone and alkyl side chains) contribute to the complete diffraction pattern, and how modest changes to a particular component orientation (e.g., backbone or side-chain tilt) influence the diffraction pattern. The effects on the polymer crystal structure of varying the alkyl side-chain length from C(12) to C(14) and C(16) are also studied. The accurate determination of the three-dimensional polymer structure allows us to examine the PBTTT electronic band structure and intermolecular electronic couplings (transfer integrals) as a function of alkyl side-chain length. This combination of theoretical and experimental techniques proves to be an important tool to help establish the relationship between the structural and electronic properties of polymer thin films.     

A general strategy for the perfluoroalkylation of arenes and arylbromides by using arylboronate esters and [(phen)CuR(F)

A versatile method for the synthesis of aryl perfluoroalkanes from arenes and aryl bromides is described. Substituted arenes or aryl bromides are converted in situ to an aryl boronate ester that readily undergoes perfluoroalkylation in air with [(phen)CuR(F)]. A broad range of aryl bromide substrates were perfluoroalkylated in good yield for the first time. [(phen)CuCF(3)] is now commercially available and has been prepared on 20?g scale.     

Procedure for the Rapid Synthesis of the Monomer 1,4-Bis(chloromethyl)-2-(2-ethylhexyloxy)-5-methoxybenzene

The alkylation of 4-methoxyphenol with 2-ethylhexyl bromide was accelerated by using potassium tert-butoxide in dimethylformamide. Subsequent chloromethylation occurred quickly using acetic acid as a cosolvent to give the poly[(2-(2-ethylhexyloxy)-5-methoxy-p-phenylene)vinylene] (MEH-PPV) monomer in 61% overall yield on a 2-mol scale.     

Unusual structures of main group organometallic compounds containing m-terphenyl ligands

The use of the m-terphenyl substituent has facilitated the synthesis of numerous unusual molecules containing main group elements. This review reports these advances as well as highlights potential synthetically useful derivatives. Finally, future applications for this ligand design are suggested.     

BiBr3 initiated cyclization-addition reactions: effect of π-nucleophile on oxocarbenium ion addition and total syntheses of (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic acid and its trans-diastereomer

For BiBr₃ initiated tandem cyclization-additions of very reactive silyl ketene acetal nucleophiles with δ-silyloxy aldehydes to afford 2,6-disubstituted THP products, diastereoselectivities range from 5-6:1 (trans-/cis-). The selectivity for axial attack on the intermediate oxocarbenium ion is inversely proportional to π-nucleophilicity. We have utilized this chemistry to convert a common starting material to both cis- and trans-diastereomers of an acid first isolated from the secretions of Viverra civetta.     

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.     

C?H Hydroxylation Using a Heterocyclic Catalyst and Aqueous H2O2

Substituted benzoxathiazines function as catalysts for the selective hydroxylation of tertiary C? H bonds. Mechanistic studies have revealed an unanticipated disparity between oxaziridine reactivity and catalyst performance and have given way to a new catalyst and an aqueous H₂O₂ reaction protocol that greatly facilitate such transformations (see scheme).

     

Novel paramagnetic AT1 receptor antagonists

Novel paramagnetic selective angiotensin AT(1) receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pK(B) estimates in the range 6.2-9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery.