Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines.
Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines.
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DOI：
10.1039/c2ob26705e
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发表时间：
2013-02-21
影响因子：
3.2
通讯作者：
David SA
中科院分区：
文献类型：
--
作者：
Kokatla HP;Yoo E;Salunke DB;Sil D;Ng CF;Balakrishna R;Malladi SS;Fox LM;David SA
以2-烷基噻唑并[4，5-c]喹啉-4-胺(CL075)为代表的Toll样受体(Toll-like Receptor，TLR)-8激动剂通过诱导T辅助1极化细胞因子的产生而激活获得性免疫应答，提示TLR8活性化合物有望成为候选疫苗佐剂，尤其是用于新生儿疫苗。在C2位带有甲基、乙基、丙基和丁基的烷基噻唑喹啉类化合物显示出类似的TLR8-激动剂活性；C2-戊基化合物的活性急剧降低，更高的同系物不活性。C2-丁基化合物具有显著的TLR7激动剂活性，是独一无二的。C2上带有支链烷基的类似物对末端立体结构的耐受性较差。实际上，C8上的所有修饰都会导致激动剂活性的丧失。C4-胺上的烷基化是不允许的，而具有短酰基(乙酰基除外)的N-酰基类似物保持了TLR8激动剂的活性，但水溶性大大降低。以C2-丁基四氮唑喹啉为先导分子的模型亚单位抗原免疫兔，可增强抗原特异性抗体效价。
Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.
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DOI：
10.4049/jimmunol.0901481
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kollmann TR;Crabtree J;Rein-Weston A;Blimkie D;Thommai F;Wang XY;Lavoie PM;Furlong J;Fortuno ES 3rd;Hajjar AM;Hawkins NR;Self SG;Wilson CB
通讯作者：
Wilson CB
影响因子：
4.4
作者：
Gorden, Keith K. B.;Qiu, Xiaohong X.;Alkan, Sefik S.
通讯作者：
Alkan, Sefik S.
影响因子：
20.3
作者：
Levy, Ofer;Suter, Eugenie E.;Wessels, Michael R.
通讯作者：
Wessels, Michael R.
Toll样受体2-激动剂的结构活性关系导致简化的单酰基脂肪肽。
影响因子：
7.3
作者：
Agnihotri, Geetanjali;Crall, Breanna M.;Lewis, Tyler C.;Day, Timothy P.;Balakrishna, Rajalakshmi;Warshakoon, Hemamali J.;Malladi, Subbalakshmi S.;David, Sunil A.
通讯作者：
David, Sunil A.
影响因子：
7.3
作者：
Agnihotri G;Ukani R;Malladi SS;Warshakoon HJ;Balakrishna R;Wang X;David SA
通讯作者：
David SA