Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs.
Two series of C-8 substituted guanine derivatives were synthesized, one bearing 2-amino substitutions and the other bearing 2-acetamide substitutions. Biological activity tests showed that almost all of them possessed some extent of antitumor activities, and were with lower toxicity against normal human liver HL7702 cells than AZD4547 (the positive control). Among them, N-[8-(4-bromo-1H-indol-3-yl)-6-hydroxy-9H-purin-2-yl]-acetamide exhibited a relatively satisfied inhibition against FGFR1 kinase with IC50 of 1.56 μM and specifically against A549 cells with IC50 of 8.28 μM and B16-F10 cells with IC50 of 6.59 μM. Above all, the introduction of large substituents such as indolyl groups at 8-position of the guanine scaffold probably achieves higher selectivity for FGFR1 as compared with AZD4547.
School of Pharmacy, Health Science Center Xi'an Jiaotong University, Xi'an 710061, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Faqing
F
Ye
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Liangfang
L
Chen
Wenzhou Central Hospital, Wenzhou 325035, China.
Lichuan
L
Hu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Tong
T
Xiao
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Shufang
S
Yu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Di
D
Chen
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Yu
Y
Wang
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Guang
G
Liang
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Zhiguo
Z
Liu
School of Pharmacy, Health Science Center Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: wangsc@mail.xjtu.edu.cn.
Sicen
S
Wang
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D006147:Guanine; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
Antitumor activity; FGFR; Guanine; Kinase inhibitor