New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
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DOI：
10.1021/acs.jmedchem.5b01135
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发表时间：
2016-02-25
影响因子：
7.3
通讯作者：
Ciulli A
中科院分区：
文献类型：
--
作者：
Baud MG;Lin-Shiao E;Zengerle M;Tallant C;Ciulli A
我们描述了基于三唑并苯并二氮杂卓骨架的溴和额外末端（BET）溴结构域抑制剂I-BET 762/JQ 1的一系列取代类似物的新合成路线。这些新的路线允许的甲氧基苯基和氯苯基环的衍生化，除了二氮杂三元中心和侧链亚甲基部分。在侧链亚甲基水平上的取代提供了靶向特异性和有效工程化的BET溴结构域的化合物，该BET溴结构域被设计为凸点和空穴方法的一部分。我们进一步证明，第二个溴结构域超过第一个溴结构域的显著选择性可以用吲哚衍生物实现，所述吲哚衍生物利用与BET溴结构域的BC环上的天冬氨酸/组氨酸保守取代的差异相互作用。
We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.