Design,Synthesis And Anti-tumor Activity Of Sorafenib Derivatives

Bis-aryl urea derivative Sorafenib is a novel oral small molecule multi-targeted receptor tyrosine kinase inhibitor.It can inhibit cancer cell growth by interrupting the RAS/RAF/MEK/ERK and VEGFR-2 signaling pathway.In this paper,tyrosine kinases and its related signal transduction pathways were introduced,and advanced progress of Sorafenib structure modification in recent years were illustrated in details.Based on this,we focus on the design,synthesis and anti-tumor activities of the new Sorafenib derivatives.In this paper,we summarized experience of modifications on the diaryl urea framework and binding mode of Sorafenib with kinase,five series of N-methyl-4-（4-Substitutedphenoxy）picolimamide derivatives(W₁-W₅ series)which add up to 78 new compounds were designed and synthesized in continuation of our interest in modifications on Sorafenib.Among all target compounds,the N-methyl-4-（4-Substitutedphenoxy）pico-limamide motif of Sorafenib was preserved as pharmacophore,and the urea framework was replaced with five different scaffolds withsulfonylaminocarbamoyl,4-Substitutedphenylpyridine-2-Formyl,5-Substituted phenyl pyridine-2-Formyl,4-Substituted phenyl pyrimidine-2-Formyl and 6-Substituted phenyl pyrimidine-4-Formyl.All the compounds have not been reported in the literature and their chemical structures were confirmed by MS and¹H-NMR.The compounds were evaluated for their anti-tumor activity against lung cancer cell line A549,human cervical cancer cell line Hela,human breast cancer cell line and human prostate cancer cell line PC-3 by MTT assay using Sorafenib as the positive control.The pharmacological results showed that 21 compounds were more active than or equal to Sorafenib against one or more cell lines.Nine compounds（WCJ-23、WCJ-24,etc）showed good cytotoxic activity against A549 cell line.Five compounds（WCJ-22、WCJ-23,etc）exhibited excellent cytotoxic activity against Hela,and 14 compounds（WCJ-22、WCJ-23,etc）displayed enhanced cytotoxic activity against MCF-7 cell line as well as the prominent selectivity to it.It is noteworthy that the most promising compound WCJ-38 showed IC₅₀ value in the nM range against MCF-7 cell line(IC₅₀=0.62μmol·L^-1),whose potency was6.79-fold higher than Sorafenib(IC₅₀=4.21μmol·L^-1).In order to determine their target,4 preferred compounds were evaluated for their activities against VEGFR-2/KDR kinase by the LANCE^?Ultra kinase assay,using Sorafenib as positive controls.The results showed that the compounds exhibited weak inhibitory activities against VEGFR-2/KDR kinase.It means that the designed compounds may act as other mechanisms or targets.The structure-activity relationships of the target compounds were discussed primarily through computer-aided drug design software docking module.5 kinds of active structural fragments containing both hydrogen bond acceptor and donor were introduced.4-Substituted phenyl pyridine-2-formyl(W₂ series)and 5-substituted phenyl pyridine-2-Formyl(W₃ series)of the structure are beneficial to increase the activity.The compounds which have sulfonylamino carbamoyl(W₁ series),4-substituted phenyl pyrimidine-2-formyl(W₄ series)and 6-substituted phenyl pyrimidine-4-formyl(W₅ series)showed poor anti-tumor activity.Through docking and cytotoxic compounds results,we can found that the substituted phenyl position of 4-Substituted phenyl pyridine-2-carboxamides(W₂ series)and 5-substituted phenyl pyridine-2-carboxamides(W₃ series)is important to the activity of the compounds.The anti-tumor activity of 5-substituted phenyl pyridine-2-formyl（W₃series）was better than that of the 4-substituted phenyl pyridine-2-formyl(W₂ series).According the anti-tumor activities and protein molecular docking results of urea structure-containing compounds,we learn that introduction of pyridine amides structure significantly increased the anti-tumor activities of the target compounds.And when the pyridine amides structure was replaced by pyrimidine amide structure,the anti-tumor activities were significantly decreased.Moreover,the results show that N-methylpyridine-2-carboxamide structure plays an important role in maintaining the activities of these compounds.They can form hydrogen bonds with the amino acid residues of VEGFR-2 kinase that make them could closely integrate with VEGFR-2 kinase.Insummary,aseriesofSorafenibderivativesthatcontainN-methyl-4-phenoxy-pyridine was design and synthesis,and screened to obtain some compounds which has strong anti-tumor activity.The QSAR analysis of Sorafenib derivatives provide optimized transformation of ideas,and pointing out the direction for further study.