Photocycloaddition Of 4,5\u27,8-trimethylpsoralen And Oleic-acid Methyl-ester - Product Structures And Reaction-mechanism

The stereochemical structures of the four adducts formed between oleic acid methyl ester (OAME) and 4,5\u27,8-trimethylpsoralen (tmPso) have been determined. Assignment of the tmPso \u27H NMR spectrum was accomplished by analogy to two coumarin model compounds and with the use of homonuclear decoupling and resonance enhancement. Assignment of the lH NMR spectra for the OAME-tmPso adducts was made by analogy to the spectra of OAME and tmPso and using 2D &resolved and COSY analyses. The configurations of the cyclobutyl rings in these adducts was determined by The stereochemical structures of the four adducts formed between oleic acid methyl ester (OAME) and 4,5\u27,8-trimethylpsoralen (tmPso) have been determined. Assignment of the tmPso \u27H NMR spectrum was accomplished by analogy to two coumarin model compounds and with the use of homonuclear decoupling and resonance enhancement. Assignment of the lH NMR spectra for the OAME-tmPso adducts was made by analogy to the spectra of OAME and tmPso and using 2D &resolved; and COSY analyses. The configurations of the cyclobutyl rings in these adducts was determined by MM2 energy minimization calculations, homonuclear \u27H NOE analysis, and comparison of products obtained with cis-OAME and trans-EAME (elaidic acid methyl ester). Only four of the eight possible disastereomeric adducts are detected. These adducts have the cis-cis- , cis-cis-HT, trans-cis- , and trans-cis-HT configurations. The lack of formation of the other isomers may be due to the geometric requirements of exciplex formation. The mechanism of the reaction was established to involve initial bond formation at the 4 position of tmPso, most likely to form a diradical intermediate. The rate of dissociation of the trans diradical is much faster than ring closure, in contrast to the cis diradical whose rate of ring closure is at least as fast as dissociation. The rate of cis-trans isomerization of the 9,lO-bond of the fatty ester portion of the diradical is faster than ring closure for the cis diradical and slower than ring closure for the trans diradical

Distinct Pigmentary and Melanocortin 1 Receptor–Dependent Components of Cutaneous Defense against Ultraviolet Radiation

Genetic variation at the melanocortin 1 receptor (MC1R) is an important risk factor for developing ultraviolet (UV) radiation–induced skin cancer, the most common form of cancer in humans. The underlying mechanisms by which the MC1R defends against UV-induced skin cancer are not known. We used neonatal mouse skin (which, like human skin, contains a mixture of melanocytes and keratinocytes) to study how pigment cells and Mc1r genotype affect the genome-level response to UV radiation. Animals without viable melanocytes (Kit(W-v)/Kit(W-v)) or animals lacking a functional Mc1r (Mc1r(e)/Mc1r(e)) were exposed to sunburn-level doses of UVB radiation, and the patterns of large-scale gene expression in the basal epidermis were compared to each other and to nonmutant animals. Our analysis revealed discrete Kit- and Mc1r-dependent UVB transcriptional responses in the basal epidermis. The Kit-dependent UVB response was characterized largely by an enrichment of oxidative and endoplasmic reticulum stress genes, highlighting a distinctive role for pigmented melanocytes in mediating antioxidant defenses against genotoxic stresses within the basal epidermal environment. By contrast, the Mc1r-dependent UVB response contained an abundance of genes associated with regulating the cell cycle and oncogenesis. To test the clinical relevance of these observations, we analyzed publicly available data sets for primary melanoma and melanoma metastases and found that the set of genes specific for the Mc1r-dependent UVB response was able to differentiate between different clinical subtypes. Our analysis also revealed that the classes of genes induced by UVB differ from those repressed by UVB with regard to their biological functions, their overall number, and their size. The findings described here offer new insights into the transcriptional nature of the UV response in the skin and provide a molecular framework for the underlying mechanisms by which melanocytes and the Mc1r independently mediate and afford protection against UV radiation

Hydroxybenzothiazoles as New Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC50-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics

Pharmaceutical Creep: U.S. Military Power and the Global and Transnational Mobility of Psychopharmaceuticals

In 2006, the United States Department of Defense developed for the first time official criteria for the use of psychopharmaceuticals “in theater”—in the physical and tactical spaces of military operations including active combat. Based on fieldwork with Army soldiers and veterans, this article explores the transnational and global dimensions of military psychopharmaceutical use in the post‐9/11 wars. I consider the spatial, material, and symbolic dimensions of what I call “pharmaceutical creep”—the slow drift of psychopharmaceuticals from the civilian world into theater and into the military corporate body. While pharmaceutical creep is managed by the U.S. military as a problem of gatekeeping and of supply and provisioning, medications can appear as the solution to recruitment and performance problems once in theater. Drawing on soldiers’ accounts of medication use, I illuminate the possibilities, but also the frictions, that arise when routine psychopharmaceuticals are remade into technologies of global counterinsurgency