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A general methodology for the synthesis of substituted quinolin-4-amines developed by us previously has been simplified. The synthesized compounds, depending on substituents, show activities in the range from 35 nM to 550 nM as antagonists of immunostimulatory oligodeoxynucleotides containing a CpG motif. A SAR analysis is presented. CpG motifs in DNA of vertebrates contain mostly 5-methylcyctosine. By contrast, the CpG motifs with unmethylated cytosine are common in bacterial DNA, and stimulate immune responses in vertebrates.' Singlestranded synthetic CpG-containing oligodeoxynucleotides and phosphorothioate oligodeoxynucleotides (CpG-ODN) are also immunostimulatory. This finding has led to the development of a simple assay in vitro for the search of compounds that inhibit the immunostimulatory effect. Several agents that are active in this in vitro assay induce remissions of rheumatoid arthritis and systemic lupus erythematosus, suggesting the involvement of CpG-DNA in these autoimmune diseases.' In our previous work we synthesized and assayed many classes of compounds and showed that several substituted 2-arylquinolin-4-amines are the most potent antagonists of the immunostimulatory CpG-ODN found to date." The assayed quinolines contained diverse 2-aryl and 4-amino groups but had no substituents at other positions of the quinolines system. This report pertains to the synthesis and biological evaluation of a series of new 2-aryl-4-[[2-(dimethylamino)ethyl]amino]quinolines that contain an additional substituent at the 6 or 7 position (Scheme 1). The [2-(dimethylamino)ethyl]amino function was chosen for all quinolines because such derivatives, in general, show high activity. Pairs of quinolines without and with the 6or 7-substituent were synthesized and assayed for a direct analysis of the effect of the substituent. The desired compounds 13 27 (Scheme 1) were synthesized by condensation of 2-(trifluoromethyl)anilines 1-5 with aryl methyl ketones 6-11 followed by cyclization of the resultant ketimines 12 by treatment with a lithium derivative of 2-(dimethylamino)ethylamine. Previously," this general methodology called for the use of analytically pure intermediate ketimines 12. As part of this work it was found that prepurification by a simple bulb-to-bulb distillation, giving 12 of about 90% purity, was adequate. In addition, tetrahydrofiiran was substituted for ether" as solvent in the subsequent cyclization reactions of 12, which resulted in slightly increased yields of the quinoline products. Compounds 13 27 were obtained by using this modified methodology. The effective concentrations (EC50) for 50% inhibition of the CpG-ODN mediated effect vary from 35 nM for 14 to 550 nM for 24 and 25 (Scheme 1). Comparison of the EC50 values for pairs of compounds composed of an identical 2-arylquinoline system, e.g. 14/18 and 15/20, reveals that the presence of a fluorine atom at the position 6 of the quinolines decreases the activity. A similar effect is observed for 6-chloro substitution (compare 13/22 and 16/23). However, the largest decrease in activity is seen for the 7-trifluoromethyl substituted quinolines (e.g. 14/24 and 15/26). Interestingly, the 4-(trifluoromethyl)phenyl substituted quinolines 17 and 21 also exhibit relatively low activities. The highest EC50 values were obtained for compounds 14 16 that are devoid of a trifluoromethyl group. These results have important ramifications for the design of new antagonists. 9 Unauthenticated Download Date | 6/3/19 2:48 AM Vol. 13, No. 1, 2007 Improved synthesis of substituted 2-aryl-N-[2-dimethylamino)ethyl] Quinolin-4-amines and their activity 13-27 R R R R R ECso, [nM]

heterocyclic communications

IMPROVED SYNTHESIS OF SUBSTITUTED 2-ARYL-N- [2-(DIMETHYLAMINO)ETHYL]QUINOLIN-4-AMINES AND THEIR ACTIVITY AS ANTAGONISTS OF IMMUNOSTIMULATORY CpG-OLIGODEOXYNUCLEOTIDES