Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 85 Configuration
Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 85 Configuration
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DOI：
10.1021/acsmedchemlett.9b00302
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发表时间：
2020-02-01
影响因子：
4.2
通讯作者：
Crews, Phillip
中科院分区：
文献类型：
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作者：
Johnson, Tyler A.;Morris, Joseph D.;Crews, Phillip
对霉唑(1)的再研究表明，对胰腺、(PANC-1)、肝(Hep_2)和结肠(Hct-116)肿瘤细胞系具有皮摩尔效应(IC_(50)=0.00016、0.00027、0.00035 mU/M)。1的重新评估提供的[阿尔法](D)数据表明瓦努阿图的霉菌丝虫标本含有8S对映体1，而不是先前报道的8R构型。半合成得到了8-O-乙酰基霉唑(2)、8-氧霉唑(8)、霉唑亚硝基苯衍生物(MND1、MND2：9a、9b)和MND3(10)，对PANC-1细胞的IC_(50)分别为0.00129、1.0、1.0mM。这些结果强调了五-2，4-二烯-L-醇残基作为其对肿瘤细胞株的细胞毒性所需的1的关键结构特征的重要性。
Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 mu M) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [alpha](D) data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 mu M, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-l-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.