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


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Abstract

Background: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.

Methods: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 Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting.

Results: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 had 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 in a dose-dependent manner. 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.

About the authors

Chunhui Nian

, The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University

Email: info@benthamscience.net

Xin Gan

School of Pharmaceutical Sciences, Wenzhou Medical University

Email: info@benthamscience.net

Qunpeng Liu

College of Chemistry and Materials Engineering, Wenzhou University

Email: info@benthamscience.net

Yuna Wu

The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University

Email: info@benthamscience.net

Miaomiao Kong

, The 1st affiliated hospital of Wenzhou Medical University

Email: info@benthamscience.net

Peiqin Zhang

School of Pharmaceutical Sciences, Wenzhou Medical University

Email: info@benthamscience.net

Mingming Jin

School of Pharmaceutical Sciences, Wenzhou Medical University

Email: info@benthamscience.net

Zhaojun Dong

School of Pharmaceutical Sciences, Wenzhou Medical University

Email: info@benthamscience.net

Wulan Li

, The 1st affiliated hospital of Wenzhou Medical University

Email: info@benthamscience.net

Ledan Wang

Wenzhou, Zhejiang, 325000, The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University

Email: info@benthamscience.net

Wenfei He

School of Pharmaceutlcal sdences, Wenzhou Medical University

Author for correspondence.
Email: info@benthamscience.net

Xiaokun Li

School of Pharmaceutical Sciences, Wenzhou Medical University

Author for correspondence.
Email: info@benthamscience.net

Jianzhang Wu

, The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University

Author for correspondence.
Email: info@benthamscience.net

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