Design, synthesis and biological evaluation of 2H-[1,4]oxazino-[2,3-f]quinazolin derivatives as potential EGFR inhibitors for non-small cell lung cancer.

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Linchang Huang, Ying Zhang, Peng Liu, Lihong Lan, Lifang Yang, Bo Wang, Tingting Cao, Liming Hu, Xuemei Qin
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引用次数: 0

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have emerged as the first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). A series of 2H-[1,4]oxazino[2,3-f]quinazolin derivatives were synthesized and evaluated as irreversible EGFR-TKIs for the treatment of NSCLC. Most of the synthesized compounds demonstrated strong inhibitory activity against the EGFR kinase and the tested cancer cells. Notably, compound 4a exhibited considerable inhibitory effects against the EGFR kinase and the EGFRL858R/T790M mutant NCI-H1975 cancer cells. Compound 4a was found to suppress cell proliferation, colony formation, cell invasion, and migration, while also inducing G0/G1 phase arrest of the cell cycle in NCI-H1975 cells. Compound 4a was docked into the active pocket of the EGFR mutant to ascertain the probable binding conformation. Overall, compound 4a was identified as a promising irreversible EGFR-TKI for the treatment of NSCLC.

2H-[1,4]恶氮基-[2,3-f]喹唑啉衍生物作为非小细胞肺癌潜在EGFR抑制剂的设计、合成及生物学评价
表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)已成为egfr突变型非小细胞肺癌(NSCLC)患者的一线治疗药物。合成了一系列2H-[1,4]恶氮基[2,3-f]喹唑啉衍生物,并评价其为治疗NSCLC的不可逆EGFR-TKIs。大多数合成的化合物对EGFR激酶和被试癌细胞表现出较强的抑制活性。值得注意的是,化合物4a对EGFR激酶和EGFRL858R/T790M突变体NCI-H1975癌细胞有明显的抑制作用。化合物4a在NCI-H1975细胞中抑制细胞增殖、集落形成、细胞侵袭和迁移,同时诱导细胞周期的G0/G1期阻滞。化合物4a被停靠在EGFR突变体的活性口袋中,以确定可能的结合构象。总的来说,化合物4a被认为是治疗NSCLC的一种有希望的不可逆EGFR-TKI。
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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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