Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds

Title:Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds

Volume: 31

Author(s): Chunhui Nian, Xin Gan, Qunpeng Liu, Yuna Wu, Miaomiao Kong, Peiqin Zhang, Mingming Jin, Zhaojun Dong, Wulan Li, Ledan Wang, Wenfei He, Xiaokun Li and Jianzhang Wu*

Affiliation:

• The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
• Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China
• The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University; Wenzhou 325027, China

Abstract: Backgroup: Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities.

Aims: The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity.

Method: The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Wester Blotting, siRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mouse xenograft assay, western blotting.

Result: 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which has better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs.

Conclusion: In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Cite this article as:

Nian Chunhui, Gan Xin, Liu Qunpeng, Wu Yuna, Kong Miaomiao, Zhang Peiqin, Jin Mingming, Dong Zhaojun, Li Wulan, Wang Ledan, He Wenfei, Li Xiaokun and Wu Jianzhang*, Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds, Current Medicinal Chemistry 2024; 31 () . https://dx.doi.org/10.2174/0109298673298420240530093525