Background: Sorafenib is an important VEGFR2/KDR inhibitor which is widely used for
the treatment of cancer.
Objective: In this paper, two series of sorafenib analogues N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4-
phenylpicolinamides(13a–k) and N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-5-phenylpicolinamides
(14a–k) were designed and synthesized.
Methods: Their structures were confirmed by various analytical methods, such as 1
H and 13
m.p., MS, HRMS. All of them were evaluated for IC50
values against three cancer cell lines (A549,
PC-3 and MCF-7).
Results: Eleven of the synthesized compounds showed moderate to excellent cytotoxicity activity
against different cancer cells, whose potency from single-digit µM to nanomolar range. And five of
them were equal to more potent than sorafenib against one or more cell lines. The most promising
compound 14c showed excellent antitumor activities against PC-3 and MCF-7 cell lines with IC50
values of 2.62±1.07 µM and 1.14±0.92 µM, which were 1.15 to 2.75-fold more active than sorafenib
(3.03±1.01 µM, 3.14±1.65 µM), respectively.
Conclusion: Structure-activity relationships (SARs) and docking studies indicated that the replacement
of diarylurea of sorafenib with phenylpicolinamide moiety benefited to the activity. The position
of aryl group and the substituents of aryl group had a great influence on antitumor activity and
selectivity. The aryl groups with the substitute of alkyl groups (-CH3
), halogen atoms (-F,Cl) were
favorable to the cytotoxicity. However, this series of compounds showed moderate activity against
VEGFR2/KDR kinase. Mechanism of target compounds was not quite clear and further study will be
carried out to identify the possible target.