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Structure-activity relationship study of bipiperidine amide 1 has identified the reverse bipiperidine amide 4a as a CC chemokine-3 (CCR3) receptor antagonist. Optimization of the structure-activity relationship of compound 4a has resulted in the identification of a CCR3 antagonist 4i as well as a CCR3 agonist 13.

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Ruthenium(II) complexes with the general formulas [Ru(H/Cl)(CO)(PPh 3)2(L)] and cis/trans-[Ru(PPh3) 2(-L)2] (L = isoquinoline-1-carboxylate or quinoline-2-carboxylate) were synthesized and characterized by IR, 1H, 13C and 31P NMR, UV-Vis spectroscopy and X-ray crystallography. The experimental studies were completed by quantum chemical calculations, which were used to describe the nature of the interactions between the ligands and the central ion, and the orbital compositions in the frontier electronic structures. Based on a molecular orbital scheme, the calculated results allowed the interpretation of the UV-Vis spectra obtained at an experimental level. The luminescence properties of the complexes were determined.

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Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

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Preparative and stereochemical aspects of reactions providing new C-10 ester and ether derivatives of the antimalarial drug dihydroartemisinin (DHA, 2) have been examined. beta-Artesunate has been prepared for the first time, and has been differentiated from the antimalarial alpha-artesunate; the latter has been incorrectly designated as the beta-epimer in Chemical Abstracts and some primary literature. New ester and ether derivatives bearing potential intercalating groups have been synthesised by means of the Schmidt, Mitsunobu and DCC coupling procedures, by acylation in the presence of DMAP, or by hydroxy activation with BF3 as catalyst. When the hydroxy group of DHA acts as a nucleophile towards activated carboxy groups in acylating agents or the DCC intermediate, alpha-esters are obtained exclusively. When the hydroxy group is activated for displacement by nucleophiles, as in the Schmidt or Mitsunobu procedures, beta-esters and beta-ethers are obtained either exclusively or predominantly. An exception is represented by the Mitsunobu procedure involving DHA and 1- and 2-naphthols, in which mixtures of epimers are obtained; however, exclusive formation of beta-aryl ethers takes place when the Schmidt procedure is used, with activation of the intermediate trichloracetimidate by SnCl2. The latter method is therefore superior to patented procedures for the preparation of beta-aryl ethers from nonbasic aryl alcohols without detectable rearrangement to C-aryl compounds. However, the Mitsunobu procedure is better when basic aromatic alcohols are used as nucleophiles. The formation of alpha-products in which the hydroxy group of DHA acts as a nucleophile is of biological significance in relation to enzyme-mediated Phase II glucuronidation of DHA, in which only the alpha-DHA glucuronide is formed.

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15N (natural abudance) NMR spectral data are reported for a series of complexes (NArCO2=pyridine-2-carboxylate, 6-methylpyridine-2-carboxylate, pyrazine-2-carboxylate, quinoline-2-carboxyate, isoquinoline-1-carboxylate, and quinoxaline-2-carboxylate), and were obtained by the INEPT method with polarisation transfer from the hydride lying trans to nitrogen.The 15N signal moves upfield by 35-50 ppm up on coordination of nitrogen to the metal, 2J(15N-1Htrans has a value of ca. 25 Hz, and 1J(103Rh-15N) lies in the range 9.1-10.1 Hz.

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Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca2+ release from human macrophages. Structure-activity relationships are discussed.

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A series of azine-imidazole aza-BODIPY analogues has been prepared by a simple synthesis from 2-azinecarboxylic acids and imidazole N-oxides. The new fluorescent complexes exhibit large Stokes shifts (up to 10 000 cm?1), fluorescence in crystalline phase, high stability and fluorescence solvatochromism.

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We report herein, a new class of simple hematoregulatory semipeptides, formally derived from the cystine-dimerized peptide pGlu-Glu-Asp-Cys-Lys-OH, where the disulfide bond has been replaced by an isosteric dicarba bridge. The structure-activity relationship (SAR) of a series of analogues incorporating replacements at positions 1 and 2 of peptide 1 led to the design of active conformationally constrained cyclic peptides (12, 13). Ring closure was achieved by cyclization of the N-terminal amino groups at position 2 of peptide 2 using pyrazine-2,3-dicarboxylic acid. Subsequent excision of the putative C-terminal scaffold domain from the active cyclic peptides resulted in the discovery of a new class of low molecular weight hematoregulatory agents exemplified by compound 16. This semipeptide analogue, comprising two D-Ser residues connected via amide bonds to the acid groups of pyrazine-2,3-dicarboxylic acid, had comparable biological activity to the lead peptide 1. The stereochemical requirements for the observed biological activity of these novel compounds were examined. Furthermore, the hematopoietic synergistic activity induced by compound 16 in stromal cell cultures was blocked by an antibody known to neutralize the hematoregulatory effect of 1, indicating a common mechanistic end point. Compounds of the class typified by 16 may form the basis for the development of novel therapeutic agents within the area of immunoregulation.

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Palladium(0)-mediated carbonylation reactions using aryl triflates, amines, and a low concentration of [11C]carbon monoxide were used in the syntheses of 13 11C-labeled amides. Lithium bromide was used as an additive to facilitate the reaction. The 11C-labeled products were obtained with decay-corrected radiochemical yields in the range of 2-63%. The radiochemical purity of the final products exceeded 98%. As an example, a reaction starting with 1.79 GBq [11C]carbon monoxide gave 0.38 GBq of LC-purified N-isopropyl-4-nitro-[11C]benzamide within 27 min from the start of the carbonylation reaction (54% decay-corrected radiochemical yield). The specific radioactivity of this compound was 191 GBq/mumol, 35 min after the end of a 10 muAh bombardment. N-Benzyliso-quinoline-1-(13C)carboxamide was prepared and analyzed by NMR for confirmation of the labeling position. The triflates 16, 20, 21, and 22 were synthesized from the corresponding alcohols and trifluoromethanesulfonic anhydride. The reference compounds 30a and 30b were prepared from the corresponding carboxylic acids and benzylamine. The other nine reference compounds 32a to 32i were synthesized from the respective acid chlorides and amines. The presented report shows that the sometimes more easily obtainable aryl triflates can be a useful alternative to the commonly used aryl halides in palladium(0)-mediated synthesis of 11C/13C-amides.

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A series of new ecteinascidin pentacyclic-derived compounds bearing aryl carboxylic amide side chains at C-22 have been designed and synthesized. The cytotoxicity evaluation confirmed their potent antitumor activity by use of eight different cell lines. Studies on the structure-activity relationship of them showed that the chemical structure of C-22 pendants have great effects on the tumor-killing activity. Notably, Compounds 6, 7 and 8 with benzo[b]thiophene-2-carboxamide pendants exhibited excellent broad-spectrum antitumor activity with the low IC50 values of 10?7 M.

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