PDF(Pubmed)
Abstract：
New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a-j, 8a-j, 9a-c, and 10a-c. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.
摘要：
设计了新的1,5-二芳基吡唑肟杂化衍生物（支架A和B），合成，然后使用多种光谱方法验证其纯度。一组已知表达EGFR和JNK-2的五种癌细胞系，包括人结直肠腺癌细胞系DLD-1，人宫颈癌细胞系Hela，人白血病细胞系K562，人胰腺细胞系SUIT-2和人肝癌细胞系HepG2用于生物学评估其对所有合成化合物7a-j的体外细胞毒性，8a-j,9a-c,和10a-c。含肟的化合物8a-j和10a-c比其非肟同源物7a-j和9a-c更具抗增殖活性。化合物8d,8g,8i,与索拉非尼相比，10c抑制EGFR的IC50值为8至21µM。化合物8i与索拉非尼一样有效地抑制JNK-2，IC50为1.0µM。此外，化合物8g在Hela细胞系的细胞周期分析中显示细胞周期停滞在G2/M期，而化合物8i显示S期和G2期联合阻滞。根据对接研究，肟杂化化合物8d,8g,8i,和10c在EGFR结合位点处表现出-12.98至32.30kcal/mol的结合自由能,而化合物8d和8i在JNK-2结合位点处具有-9.16至-12.00kcal/mol的结合自由能。
