Tags

Type your tag names separated by a space and hit enter

Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma.
Biochem Biophys Res Commun. 2018 11 02; 505(3):761-767.BB

Abstract

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]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-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 IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and 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)-β-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.

Authors+Show Affiliations

Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, 518055, PR China. Electronic address: yaohong20055@hotmail.com.Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China. Electronic address: songleizhu@xzhmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30293685

Citation

Gao, Xiaoge, et al. "Oral Administration of Indole Substituted Dipyrido[2,3-d]pyrimidine Derivative Exhibits Anti-tumor Activity Via Inhibiting AKT and ERK1/2 On Hepatocellular Carcinoma." Biochemical and Biophysical Research Communications, vol. 505, no. 3, 2018, pp. 761-767.
Gao X, Cen L, Li F, et al. Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma. Biochem Biophys Res Commun. 2018;505(3):761-767.
Gao, X., Cen, L., Li, F., Wen, R., Yan, H., Yao, H., & Zhu, S. (2018). Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma. Biochemical and Biophysical Research Communications, 505(3), 761-767. https://doi.org/10.1016/j.bbrc.2018.09.120
Gao X, et al. Oral Administration of Indole Substituted Dipyrido[2,3-d]pyrimidine Derivative Exhibits Anti-tumor Activity Via Inhibiting AKT and ERK1/2 On Hepatocellular Carcinoma. Biochem Biophys Res Commun. 2018 11 2;505(3):761-767. PubMed PMID: 30293685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma. AU - Gao,Xiaoge, AU - Cen,Lanqi, AU - Li,Fangyuan, AU - Wen,Ren, AU - Yan,Hongru, AU - Yao,Hong, AU - Zhu,Songlei, Y1 - 2018/10/04/ PY - 2018/09/03/received PY - 2018/09/19/accepted PY - 2018/10/9/pubmed PY - 2019/5/29/medline PY - 2018/10/9/entrez KW - AKT KW - ERK1/2 KW - Hepatocellular carcinoma KW - Indole KW - Multi-component reactions KW - Pyrido[2,3-d]pyrimidine SP - 761 EP - 767 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 505 IS - 3 N2 - 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]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-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 IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and 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)-β-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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/30293685/Oral_administration_of_indole_substituted_dipyrido[23_d]pyrimidine_derivative_exhibits_anti_tumor_activity_via_inhibiting_AKT_and_ERK1/2_on_hepatocellular_carcinoma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(18)32053-9 DB - PRIME DP - Unbound Medicine ER -