225782-55-8Relevant articles and documents
Design, synthesis, and biological evaluation of indole-based hydroxamic acid derivatives as histone deacetylase inhibitors
Jiang, Bei-Er,Hu, Jiaxin,Liu, Hao,Liu, Zhitao,Wen, Yu,Liu, Mingyao,Zhang, Han-Kun,Pang, Xiufeng,Yu, Li-Fang
, (2021/10/19)
The equilibrium between histone acetylation and deacetylation plays an important role in cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine ε-amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o, was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC50 = 1.16 nM) and HDAC6 (IC50 = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC50 values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively.
Synthesis of some analogs of indole phytoalexins brassinin and methoxybrassenin B and their positional isomers
Kutschy, Peter,Dzurilla, Milan,Takasugi, Mitsuo,Sabova, Adriana
, p. 348 - 362 (2007/10/03)
Treatment of indole-3-carboxylic acid with phosphorus trichloride and subsequent reaction of the obtained acid chloride with potassium thiocyanate afforded indol-3-ylcarbonyl isothiocyanate (13). Its treatment with sodium hydrogensulfide in the presence of methyl iodide lead to the corresponding methyl dithiocarbamate, an oxo derivative of brassinin (oxobrassinin, 14), which by methylation with methyl iodide afforded brassenin B (8). Corresponding 2-isomers, 21 and 23, were obtained by an analogous sequence, starting from indole-2-carboxylic acid. During the preparation of isooxobrassinin (21), which appeared to be unstable in the basic reaction medium, also an imidazo[3,4-a]indole derivative 22 has been isolated as an unexpected side product. Related oxobrassinin analogs and their 2-isomers were prepared by treatment of indol-3-and indol-2-ylcarbonyl isothiocyanate with methanol and amines. In the case of isothiocyanate 13, besides the expected products of nucleophilic addition to NCS group (monothiocarbamate 25a and thiourea derivatives 25b-25g), also the substitution products were obtained. Their formation could be explained by partial decomposition of the starting isothiocyanate to an unstable ketene, which reacts with methanol and amines to afford the corresponding methyl carboxylate 26a and carboxamides 26b-26g. Antifungal activity of the prepared compounds has been examined, using the fungus Bipolaris leersiae. All of the compounds exhibited lower activity than phytoalexin brassinin.
