Molecular Diversity ( IF 3.9 ) Pub Date : 2020-10-11 , DOI: 10.1007/s11030-020-10147-6 Ivana Perković 1 , Maja Beus 1 , Dominique Schols 2 , Leentje Persoons 2 , Branka Zorc 1
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Abstract
In this paper, we report the synthesis of novel hybrids 2–14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2–13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI50 values between 0.7 and 8.6 µM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations.
Graphic abstract
中文翻译：
衣康酸杂化物作为潜在的抗癌剂
摘要
在本文中，我们报告了基于衣康酸和氟苯胺、吡啶、吲哚和喹啉支架的新型杂化物2-14的合成。衣康酸是一种天然存在的化合物，具有迈克尔受体部分，这是几种抗癌和抗病毒药物的关键结构特征，负责药物与特定蛋白质的半胱氨酸残基的共价结合。杂种的芳香部分也来自被报道为抗癌或抗病毒剂的物质。用于获得酰胺酯杂化物 2-13 的合成路线使用衣康酸单甲酯或衣康酰氯单甲酯和相应的胺作为起始材料。二聚体14和15使用标准偶联条件（HATU/DIEA），由衣康酸和相应的氨基衍生物制备具有两个氨基吲哚或甲氟喹部分的。所有杂种在体外对几乎所有评估的肿瘤细胞系（MCF-7、HCT 116、H460、LN-229、Capan-1、DND-41、HL-60、K-562、Z-138）均发挥抗癌作用）。一般来说，实体瘤细胞比血液癌细胞更敏感。MCF-7 乳腺癌细胞系似乎最敏感。具有氯喹核心和甲氟喹同型二聚体15的酰胺酯12显示出最高的活性，GI 50值介于 0.7 和 8.6 µM 之间。此外，化合物15还对低微摩尔浓度的寨卡病毒和柯萨奇病毒 B4 发挥抗病毒活性。
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