Discovery of anti-hepatoma agents from 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine by inhibiting PI3K/AKT/NF-κB pathway activation

Eur J Med Chem. 2021 Dec 5:225:113796. doi: 10.1016/j.ejmech.2021.113796.

Yan-Qiu Zhou ¹, Yue Sun ², Han-Lin Luo ¹, Zhong-Fei Gao ², Hong-Qin Zhang ¹, Qing-Guo Meng ³, Xian-Yong Bai ⁴, Gui-Ge Hou ⁵, Yun Hou ⁶

Affiliations

1 School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, PR China.
2 School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China.
3 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
4 School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, PR China. Electronic address: xybai1963@126.com.
5 School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China. Electronic address: guigehou@163.com.
6 School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, PR China. Electronic address: houyun820424@163.com.

PMID: 34450496 DOI: 10.1016/j.ejmech.2021.113796

Abstract

In order to obtain new anti-hepatoma drugs with low toxicity, some 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 4a-t) were synthesized in this study. Many of them showed significant anti-hepatoma effects against HCC cells and low toxicity toward HHL-5 cells. Combined with their anti-hepatoma activity and toxicity, 4-CF₃-substituted 4k was selected as an effective lead compound. Preliminary mechanistic studies revealed that 4k could up-regulate the expression levels of Bax and Caspase-3 proteins, down-regulate the expression levels of Bcl-2 protein, promote significant Apoptosis of HepG2, and block cells in G2-M phase to prevent cells from completing mitosis. Also, 4k could significantly inhibit the activation of PI3K/Akt/NF-κB pathway by blocking the phosphorylation of PI3K, Akt, NF-κB/p65 and IFN-γ-induced nuclear transport. Docking analysis showed that 4k could reasonably bind to the active sites of Bcl-2, NF-κB/p65, PI3K and Akt. This result suggested that 4k could be used as a new type of NF-κB Inhibitor, which provides a scientific basis for further research into the treatment of hepatoma.

Keywords

1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines; Anti-hepatoma agents; Apoptosis; Cell cycle; PI3K/AKT/NF-κB pathway.

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