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A new strategy for the synthesis of vinyl ketones has been achieved. Hitherto unknown and easily accessible, beta-phenylseleno-N-methoxy-N- methylpropanamide, obtained through two simple reactions, served as a building block for convenient access to vinyl ketones. The N-methoxy-N-methyl amide moiety ensured no overaddition of the Grignard reagent and, hence, the excellent formation of beta-phenylseleno ketones; oxidative work-up with hydrogen peroxide provided ready access to the vinyl ketones with concomitant loss of phenylselanol. Georg Thieme Verlag Stuttgart · New York.

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A new class of chiral calix[4]arene-based [2]catenanes was synthesized in excellent yields of 51-80%. They exhibit unique dynamic properties according to variable temperature NMR experiments. The enantiomeric pure (+)-catenane was prepared in 66% yield starting from (-)-calix[4]arene.

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New iso-vernolic and iso-linoleic acids have been prepared in order to study their potential inhibition action during in vivo desaturation of oleic acid in vegetal sources. – Keywords: Delta12-desaturase / modified fatty acids / Z,omega-octenyl bromides / iso-linoleic acids / iso-vernolic acids

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The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58 % overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43 % overall yields. The ?5 acids displayed the best IC50’s (24-38 muM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 muM). The ?9 acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 muM and the 9-pentacosynoic acid not inhibiting the enzyme at all. Fatty acid chain length and position of the unsaturation was important for the observed inhibition. None of the synthesized fatty acids were toxic (IC50 > 500 muM) towards peripheral blood mononuclear cells. Molecular modeling studies indicated the structural determinants underlying the biological activity of the most potent compounds. These results provide new insights into the structural requirements that must be present in fatty acids so as to enhance their inhibitory potential towards HIV-RT.

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CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking alpha-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-alpha-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3?) on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble alpha-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new alpha-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.

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The structures of layers of three different dodecylcarboxybetaine surfactants adsorbed at the air-water interface have been determined by neutron reflection. The zwitterionic compounds differed in the length of the spacer separating the quaternary ammonium and carboxylate groups, which was (CH2)1, (CH2)4, or (CH2)8. The limiting area per molecule was found to be 45, 52, or 84 A2, respectively, and compared reasonably with results from surface tension showing that the Gibbs prefactor is 1 in each case. Isotopic labeling was used to distinguish between the position of the alkyl and spacer groups in the layer. The spacer was found to be well-immersed in water for the (CH2)1 and (CH2)4 spacers but significantly above water for the (CH2)8 spacer. The distribution of the (CH2)8 spacer along the surface normal was found to be similar to that of the dodecyl group; i.e., it projects out of the water, contrary to an earlier hypothesis that it forms a loop. Comparison of the overlap of water with dodecyl and spacer groups also indicates that the (CH2)8 spacer is well out of the water. This in turn suggests that the anionic carboxylic acid group, which is dissociated in solution, is not ionized in the adsorbed layer. A further observation is that the dodecylcarboxybetaine with the (CH2)8 spacer reaches surface saturation at one-tenth of the critical micelle concentration. This is highly unusual and is attributed to the long spacer destabilizing the micelle relative to the surface layer.

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The present invention relates to substituted macrocyclic indole derivatives of general formula (I) in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

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DMAKO-05, a novel dimethylation of alkannin oxime derivative, exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma. However, its potent cytotoxicity is not closely associated with reactive oxygen species (ROS) and bioreductive alkylation. Its specific antitumor target(s) has still remained elusive. To recognize the molecular target(s) of DMAKO-05 and its analogs, four biotinylated DMAKO derivatives were designed and prepared. The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction, which kept its anticancer activity. Moreover, the cell-based investigation demonstrated that replacement of the linker C4chain with another alkyl chain (C6or C8) gave rise to the enhancement of cytotoxicity. Among these biotinyl derivatives, both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells. As expected, they might be thought as ideal chemical probes. Collectively, our present work could provide an available approach for the identification of the potential antineoplastic target(s) of DMAKO derivatives.

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17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca 2+-overload with EC50 ? 1-2 nM. Structure-activity studies revealed that a cis-Delta11,12- or Delta14,15- olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Delta14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.

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The invention belongs to the field of chemical preparation, relates to a syli handkerchief standard intermediate and syli handkerchief standard preparation method; the states the syli handkerchief standard intermediate is compound SLP – 4 compound SLP – 7 compound SLP – 8 compound SLP – 10 the invention provides a method for preparing syli handkerchief standard with rational route, raw materials are easy, low cost, low operation difficulty, small pollution to the environment and the like, so that the method of the present invention can meet the requirements of industrial production on a large scale. (by machine translation)

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