Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]ous aromatic aldehyde 2, and 2,6diaminopyrimidin-4(3H)-one 3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound 4p that showed the lowest dosage of ICSO to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKTand ERK1/2 signaling pathways in vitro. To improve the solubility of compound 4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)beta-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted 4p effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted 4p is an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies. (C) 2018 Elsevier Inc. All rights reserved.