Synthesis, activity and docking studies of phenylpyrimidine-carboxamide Sorafenib derivatives.
Two series of Sorafenib derivatives bearing phenylpyrimidine-carboxamide moiety (16a-g and 17a-p) were designed, synthesized and evaluated for the IC50values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50values of 6.35±0.43μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50values of 3.39±0.37μM. Structure-activity relationships (SARs) and docking studies indicated that the second series (17a-p) showed more active than the first series (16a-g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
Wenhui
W
Wang
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
Chunjiang
C
Wu
Fushun Center for Drug Control, Fushun 113000, China.
Jianqiang
J
Wang
Jiangxi Province Institute of Materia Medica, Nanchang 330000, China.
Rong
R
Luo
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
Caolin
C
Wang
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
Xiaobo
X
Liu
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
Jiqing
J
Li
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. Electronic address: zhuwf@jxstnu.edu.cn.
Wufu
W
Zhu
School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. Electronic address: zhengpw@126.com.
Pengwu
P
Zheng
D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011743:Pyrimidines; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2
Antitumor activity; Docking; Phenylpyrimidine; Sorafenib; Synthesis; VEGFR2/KDR