Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A
Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A
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DOI：
10.1016/j.bmcl.2012.11.036
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发表时间：
2013-01-01
影响因子：
2.7
通讯作者：
Frederick, Raphal
中科院分区：
文献类型：
--
作者：
Dolusic, Eduard;Larrieu, Pierre;Frederick, Raphal
tsisikammines是一种海洋生物碱，其结构基于吡咯亚胺醌支架。这些及相关化合物因其各种有趣的生物学特性而受到关注，包括细胞毒性、拓扑异构酶抑制、抗菌、抗真菌和抗疟疾活性。吲哚胺2,3-双加氧酶（IDO1）作为肿瘤免疫逃避机制的重要因子，已成为公认的治疗靶点。在这篇初步的通讯中，我们报道了齐虫胺衍生物对IDO1的抑制活性。Tsitsikammamine A类似物11b在酶测定中显示亚微摩尔效力。许多衍生物在细胞试验中也有活性，而对色氨酸2,3-双加氧酶（TDO）（一种功能相关的酶）显示很少或没有活性。这种IDO1抑制活性是合理的分子模拟研究。因此，这类化合物作为开发新的药用IDO1抑制剂的先导化合物的潜在来源，引起了人们的兴趣。(c) 2012 Elsevier Ltd.版权所有。
Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity.Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors. (c) 2012 Elsevier Ltd. All rights reserved.