In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.

MicroRNA-21, as an oncogenic miRNA, has caught great attention for medicinal chemists to develop its novel inhibitors for cancer therapy. In the present study, we designed 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as miR-21 inhibitor candidates on the basis of scaffold hopping. Eighteen compounds were synthesized. The inhibitory activities of synthesized compounds against the expression of miR-21 were evaluated using stem loop RT-qPCR and compound 1j was discovered as the most potent compound, which displayed a time and concentration dependent inhibition manner. In addition, various functional assays such as the expression of miR-21 target gene detected by Western blotting and the cell growth and apoptosis detected by flow cytometric analysis were checked in Hela (human epithelioid cervix carcinoma) and U-87 MG (human glioblastoma) cells to confirm its activity. The results indicate that compound 1j can enhance apoptosis, retard proliferation, and up-regulate PDCD4, a target protein of miR-21. In addition, the compound 1j does not influence the expression of multiple miRNAs and the genes that participate in miRNA universal biosynthesis pathway. These results strongly support the assumption that title compounds can serve as a small molecule inhibitor of miR-21.4-Benzoylamino-N-(prop-2-yn-1-yl)benzamides (1) have been discovered as miR-21 inhibitor on the basis of scaffold hopping.

•A series of [1,2,4]triazolo[1,5-a]pyridinylpyridines were synthesized.•All title compounds displayed inhibitory activity against HCT-116, U-87 MG and MCF-7 cell lines.•The SAR of target compounds was preliminarily discussed.•The compounds 1c and 2d with potent antiproliferative activities were tested for their effects on the AKT and p-AKT473.•1c exhibited potent anticancer effect in vivo.A series of [1,2,4]triazolo[1,5-a]pyridinylpyridines were synthesized and characterized. Their antiproliferative activities in vitro were evaluated by MTT against three human cancer cell lines including HCT-116, U-87 MG and MCF-7 cell lines. The SAR of target compounds was preliminarily discussed. The compounds 1c and 2d with potent antiproliferative activities were tested for their effects on the AKT and p-AKT473. The anticancer effect of 1c was evaluated in mice bearing sarcoma S-180 model. The results suggest that the title compounds are potent anticancer agents.A series of [1,2,4]triazolo[1,5-a]pyridinylpyridines were synthesized and their anticancer effects were evaluated in vitro and in vivo.

2-Aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one has been proposed as a novel scaffold of EGFR inhibitor based on scaffold hoping. In the present study, a series of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one derivatives were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against two human cancer cell lines, including A431 and A549. The SAR of the title compounds was preliminarily discussed. The compounds with ideal inhibition were evaluated through ELISA-based EGFR-TK assay. Compound 6c showed the best activity against A431 and EGFR tyrosine kinase. These findings suggest that title compounds are EGFR inhibitors with novel structures.2-Aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one was discoved as novel structure of EGFR inhibitor based on scaffold hopping.