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5-(1H-吲哚-3-基)-N-芳基-1,3,4-恶二唑-2-胺作为Bcl-2抑制性抗癌剂的合成与评价

Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents.

作者信息

Hamdy Rania, Ziedan Noha I, Ali Samia, Bordoni Cinzia, El-Sadek Mohamed, Lashin Elsaid, Brancale Andrea, Jones Arwyn T, Westwell Andrew D

机构信息

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK; Faculty of Pharmacy, Zagazig University, Egypt.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK; National Research Centre, Cairo, Egypt.

出版信息

Bioorg Med Chem Lett. 2017 Feb 15;27(4):1037-1040. doi: 10.1016/j.bmcl.2016.12.061. Epub 2016 Dec 27.

DOI:10.1016/j.bmcl.2016.12.061
PMID:28087272
Abstract

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

摘要

基于我们之前的先导化合物8a，设计、合成了一系列5-(1H-吲哚-3-基)-N-芳基-1,3,4-恶二唑-2-胺8a-j，并在体外作为潜在的促凋亡Bcl-2抑制性抗癌剂进行了测试。通过吲哚-3-羧酸酰肼(5)与取代异硫氰酸酯6a-j之间的环化反应，随后使用1,3-二溴-5,5-二甲基海因对相应的硫代氨基脲7a-j进行氧化环化脱硫，很容易完成目标化合物的合成。发现该系列8a-j的活性化合物在表达Bcl-2的人癌细胞系中具有亚微摩尔IC值；值得注意的是，发现2-硝基苯基类似物8a表现出强效活性，并且化合物8a和8e与已确立的基于天然产物的Bcl-2抑制剂棉酚具有相当的Bcl-2结合亲和力(ELISA测定)。分子建模研究有助于进一步合理化抗凋亡Bcl-2结合，并确定化合物8a和8e作为Bcl-2抑制性抗癌剂进一步开发的候选物。

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