Namur Medicine & Drug Innovation Center, Namur Research Institute for Life Sciences, University of Namur, 61 Rue de Bruxelles, B-5000 Namur, Belgium.
Bioorg Med Chem Lett. 2013 Jan 1;23(1):47-54. doi: 10.1016/j.bmcl.2012.11.036. Epub 2012 Nov 22.
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.
西松烷胺类化合物是一类海洋生物碱，其结构基于吡咯并[2,3-f]喹喔啉骨架。由于具有各种有趣的生物特性，包括细胞毒性、拓扑异构酶抑制、抗菌、抗真菌和抗疟活性，这些化合物和相关化合物引起了人们的关注。吲哚胺 2,3-双加氧酶 (IDO1) 是一个成熟的治疗靶点，作为肿瘤免疫逃逸机制中的一个重要因素。在本初步通讯中，我们报告了西松烷胺衍生物对 IDO1 的抑制活性。在酶促测定中，西松烷胺 A 类似物 11b 显示出亚微摩尔的效力。一些衍生物在细胞测定中也具有活性，而对色氨酸 2,3-双加氧酶 (TDO) 的活性很低或没有，TDO 是一种功能相关的酶。通过分子建模研究可以解释这种 IDO1 抑制活性。因此，人们对这类化合物产生了兴趣，认为它们可能是开发新的具有药用价值的 IDO1 抑制剂的潜在先导化合物来源。
