Design, Synthesis, In silico and In Vitro Anticancer Activity of Novel Bis‐Furanyl‐Chalcone Derivatives Linked through Alkyl Spacers

Abstract

AbstractA 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 5 a–c in which the furan ring designed to be a B‐ring were obtained from the Knoevenagel condensation reactions of the appropriate bis(acetyl) compounds 3 a–c with two equivalents of furan‐2‐aldehyde. Likewise, the condensation of bis(aldehydes) 7 a–c with two equivalents of 2‐acetylfuran afforded the corresponding chalcones 9 a–c, 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 9 a and 9 c 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 9 a and 9 c. 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 9 a and 9 c, 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 9 a and 9 c showed a significant anticancer activity against lung and skin cancer cell lines compared with known chemotherapeutic drug (doxorubicin).