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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Carbonic anhydrase activators - part 21. Novel activators of isozymes I, II and IV incorporating carboxamido and ureido histamine moieties.
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Carbonic anhydrase activators - part 21. Novel activators of isozymes I, II and IV incorporating carboxamido and ureido histamine moieties.

机译：碳酸酐酶激活剂-第21部分。结合了羧酰胺基和脲基组胺部分的同工酶I，II和IV的新型激活剂。

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摘要

Reaction of histamine with tetrabromophthalic anhydride and protection of its imidazole moiety with tritylsulfenyl chloride, followed by hydrazinolysis, afforded N-1-tritylsulfenyl histamine, a key intermediate which was further derivatized at its aminoethyl moiety. Carboxamido derivatives were obtained by reaction of the key intermediate with carboxylic acid anhydrides, acyl chlorides or carboxylic acids in the presence of carbodiimides. Reaction of the same key intermediate with isocyanates, isothiocyanates, cyanamide or dicyandiamide afforded another series of compounds. Deprotection of the above-mentioned intermediates with hydrochloric acid in dioxane afforded two series of compounds, histamine derivatives possessing carboxamido, ureido, thioureido or guanidino moieties in their molecule. The new derivatives were assayed as activators of three carbonic anhydrase (CA) isozymes, hCA I, hCA II (cytosolic forms) and bCA IV (membrane-bound form, h = human, b = bovine isozyme). Efficient activation was observed against all three isozymes, but especially against hCA I and bCA IV, with affinities in the nanomolar range for the best compounds. hCA II was, on the other hand, activatable with affinities around 10-25 nM. This new class of CA activators might lead to the development of drugs/diagnostic agents for the CA deficiency syndrome, a genetic disease of bone, brain and kidneys.
机译：组胺与四溴邻苯二甲酸酐反应，并用三苯甲基磺酰氯保护其咪唑部分，然后进行肼解作用，得到N-1-三苯甲基磺酰组胺，其为关键中间体，其在其氨乙基部分进一步衍生。通过在碳二亚胺存在下使关键中间体与羧酸酐，酰氯或羧酸反应获得羧酰胺衍生物。相同的关键中间体与异氰酸酯，异硫氰酸酯，氰酰胺或双氰胺反应，得到另一系列化合物。在二恶烷中用盐酸使上述中间体脱保护，得到两个系列的化合物，其分子中具有羧酰胺基，脲基，硫脲基或胍基部分的组胺衍生物。测定了新衍生物作为三种碳酸酐酶（CA）同工酶的激活剂，它们分别是hCA I，hCA II（胞质形式）和bCA IV（膜结合形式，h =人，b =牛同工酶）。观察到针对所有三种同工酶的有效活化，尤其是针对hCA I和bCA IV的活化，最佳化合物的亲和力在纳摩尔范围内。另一方面，hCA II可被激活，亲和力约为10-25 nM。这类新型的CA激活剂可能会导致针对CA缺乏综合症（一种骨骼，脑和肾脏的遗传性疾病）的药物/诊断剂的开发。

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