Design, Synthesis And Antitumor Activity Of 7-azaindole BRAF Inhibitor

Cell signal transduction is closely related to the occurrence,development,recurrence,and metastasis of tumors,so tumor signal transduction pathways have become an effective target for anti-tumor drug research.Abnormal RAS/RAF/MEK/ERK signal transduction pathways account for approximately 40% of human malignant tumors,with mutations in RAF and its upstream activator RAS being the most common.BRAF mutations have been found in various human cancers,such as thyroid cancer,colon cancer,and melanoma.Although a large number of BRAF inhibitors have been reported,there are still problems such as low bioavailability,low selectivity,drug resistance,and serious toxic and side effects.Therefore,the development of efficient and safe novel BRAF selective inhibitors has significant clinical application value.Based on the analysis of the action modes of existing BRAF inhibitors and BRAF kinases,four series of target compounds are designed based on 7-azaindole.And the synthesis route of the target compounds is designed and optimized through inverse synthesis analysis.At the same time,the effects of reaction solvent,reaction temperature,feed ratio,and feed sequence on the yield are fully investigated,and a better synthesis route and process was ultimately obtained.14 A series target compounds were obtained through acylation,substitution,and Suzuki-Miyaura coupling,and 14 B series target compounds were obtained through Mannich reaction based on the A series target compounds.2 C and 2 D series target compounds were obtained through sulfonylation,Suzuki-Miyaura,bromination,addition,elimination,and hydrolysis reactions.Human colon cancer cell line（HCT-116）and human breast cancer cell line（MCF-7）are used as test cell lines,and the BRAF inhibitor Vemurafenib was used as positive control drug.The results showed that the target compound had good inhibitory activity against HCT-116 and MCF-7,and compounds A5,B6,B9,B14,C1 and D2 exhibited significantly better anti-tumor proliferation activity than Vemurafenib.Based on the preliminary screening activity,the IC₅₀ values of some compounds against HCT-116 and MCF-7 cells were further measured.Among them,compound B14 showed a good inhibitory effect in both cell lines(IC₅₀（HCT-116）= 8.45 μM,IC₅₀（MCF-7）= 14.54μM).The preliminary structure-activity relationship showed that the 5-substituted aryl group on the 7-azaindole ring had a significant impact on the inhibitory activity.In the A series compounds,the overall inhibitory activity order was: 3-hydroxyphenyl >3-cyanophenyl ≥ 3-pyridyl.In the B series compounds,the overall inhibitory activity sequence is: 3-pyridyl ≥ 3-cyanophenyl > 3-carboxyphenyl.In addition,the introduction of Mannich base at the 3 position of the 7-azaindole ring can significantly improve the canti-tumor proliferation activity.