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Design, Synthesis, In silico and In Vitro Anticancer Activity of Novel Bis-Furanyl-Chalcone Derivatives Linked through Alkyl Spacers
ChemistrySelect ( IF 1.9 ) Pub Date : 2021-06-24 , DOI: 10.1002/slct.202100884
Esraa M. Fathi 1 , Farid M. Sroor 2 , Karima F. Mahrous 3 , Magda F. Mohamed 4 , Khaled Mahmoud 5 , Marwan Emara 6 , Ahmed H. M. Elwahy 1 , Ismail A. Abdelhamid 1
Affiliation  

A novel series of bis(furan-based chalcone) derivatives linked to aliphatic linkers, with the furan units at the A- or B-rings, were synthesized and evaluated as anticancer agents. Chalcones 5ac in which the furan ring designed to be a B-ring were obtained from the Knoevenagel condensation reactions of the appropriate bis(acetyl) compounds 3ac with two equivalents of furan-2-aldehyde. Likewise, the condensation of bis(aldehydes) 7ac with two equivalents of 2-acetylfuran afforded the corresponding chalcones 9ac, in which the furan rings represent the A-rings of the chalcones, in excellent yields. The synthesized compounds have been fully characterized by 1H-NMR, 13C-NMR, and elemental analysis. The in vitro anticancer activity of the prepared compounds was tested against A549, HCT116, HePG2, PC3, A431 and BJ1 cell lines using MTT assay, gene expression analysis of skin and lung cancer related genes, comet assay, and DNA fragmentation assy. Compounds 9a and 9c were found to be the most promising, with IC50 (24.9 and 13.7 μg/ml, respectively) against A549 compared with doxorubicin (IC50, 28.3 μg/ml) and IC50 (26.1 and 14.4 μg/ml, respectively) against A431 in comparison to doxorubicin (IC50, 24.9 μg/ml). Comapred with neagtive control cell lines, the gene expression levels of hBD-2 and hBD-3 genes were decreased singnificantly (P<0.05) in positive control and skin cancer cell lines (A431) treated with compounds 9a and 9c. The expression levels of FOSB and IL-8 genes were increased singnificantly (P<0.05) in positive control and lung cancer cell lines (A549 and A541) treated with compounds 9a and 9c, respectively, comapred with neagtive control cell lines. The DNA damage was increased significantly (P<0.001) in treated skin and lung cell lines samples compared with negative control. The negative control skin and lung cancer cell lines showed a significant decrease (P< 0.05) in DNA fragmentation rate compared with positive control. On the other hand, the DNA fragmentation rates were increased significantly (P<0.001) in treated skin and lung cell lines samples compared with negative control. In summary, the synthesized compounds 9a and 9c showed a significant anticancer activity against lung and skin cancer cell lines compared with known chemotherapeutic drug (doxorubicin).

中文翻译:

通过烷基间隔连接的新型双-呋喃基-查尔酮衍生物的设计、合成、计算机模拟和体外抗癌活性

合成了一系列新的双(呋喃基查耳酮)衍生物,它们与脂肪族接头相连,呋喃单元位于 A 或 B 环上,并被评估为抗癌剂。查耳酮5 a - c其中设计为 B 环的呋喃环是从适当的双(乙酰​​)化合物3 a - c与两当量的呋喃-2-醛的 Knoevenagel 缩合反应中获得的。同样,双(醛)7 ac与两当量的 2-乙酰呋喃缩合得到相应的查耳酮9 ac,其中呋喃环代表查耳酮的 A 环,产率极好。合成的化合物已通过1 H-NMR、13 C-NMR 和元素分析进行了充分表征。使用MTT试验、皮肤癌和肺癌相关基因的基因表达分析、彗星试验和DNA片段化分析测试了制备的化合物对A549、HCT116、HePG2、PC3、A431和BJ1细胞系的体外抗癌活性。化合物99 Ç被认为是最有前途的,用IC 50(24.9和13.7微克/毫升,分别地)针对A549用阿霉素进行比较(IC 50,28.3微克/毫升)和IC 50(分别为 26.1 和 14.4 μg/ml)与多柔比星(IC 50,24.9 μg/ml)相比,A431 。与neagtive对照细胞系Comapred,β防御素2和β防御素3种基因的基因表达水平在用化合物处理的阳性对照和皮肤癌细胞系(A431)singnificantly降低(P <0.05)99 Ç。FOSB和IL-8基因的表达水平在用化合物处理的阳性对照和肺癌细胞系(A549和A541)singnificantly增加(P <0.05)99 Ç,分别与阴性对照细胞系相比较。与阴性对照相比,经处理的皮肤和肺细胞系样品的 DNA 损伤显着增加(P<0.001)。与阳性对照相比,阴性对照皮肤和肺癌细胞系的 DNA 断裂率显着降低(P < 0.05)。另一方面,与阴性对照相比,经处理的皮肤和肺细胞系样品的 DNA 断裂率显着增加(P<0.001)。总之,合成的化合物99 Ç显示出与已知的化疗药物(阿霉素)比较抗肺和皮肤癌细胞系显著抗癌活性。
更新日期:2021-06-24
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