Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A

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• 作者：Eduard Doluš ; ić ; ^a ; ^{eduard.dolusic@fundp.ac.be} ; Pierre Larrieu^b ; C&#233 ; line Meinguet^a ; Delphine Colette^c ; Arnaud Rives^d ; S&#233 ; bastien Blanc^c ; Thierry Ferain^c ; Luc Pilotte^b ; Vincent Stroobant^b ; Johan Wouters^a ; Benoî ; t Van den Eynde^b ; Bernard Masereel^a ; Evelyne Delfourne^d ; Raphaë ; l Fr&#233 ; d&#233 ; rick^a ; ^{raphael.frederick@fundp.ac.be}
• 关键词：IDO1 ; indoleamine 2 ; 3-dioxygenase ; TDO ; tryptophan 2 ; 3-dioxygenase ; NHDF ; normal fibroblast cell lines ; MTT ; (3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide ; EDTA ; ethylenediaminetetraacetic acid ; IMAC ; immobilized metal ion affinity chromat
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：23
• 期：1
• 页码：47-54
• 全文大小：955 K

文摘

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.