Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators

Hongyu Hu,Zhaolin Zhang,Xianfu Lin,Qi Wu,Shengxian Zhao,Yin Cao,Fengming He,Jiangang Huang

doi:10.3390/molecules27051698

Abstract

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a–9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

Highlights

Introduction iationsNuclear receptors are important targets for drug development, which are related to the therapeutic effects of 16% of small molecule drugs [1]
9h can induce Nur77 expression and nuclear export, suggesting that 9h may mediate apoptosis through Nur77-Bcl-2 pathway. These findings prove that it is a feasible approach to develop anti-gastric cancer drugs targeting Nur77, and compound 9h can be used as a lead compound for further studies
The general chemistry for the synthesis of 1-(2-(6-methoxynaphthalen-2-yl)-6-methylni cotinoyl)-4-substituted semicarbazide/thiosemicarbazide compounds 9a–9w is outlined in Scheme 2. (E)-3-(dimethylamino)-1-(6-methoxynaphthalen-2-yl)prop-2-en-1-one (3) was prepared by the reaction of 6-methoxy-2-acetonaphthone (1) with N-dimethylformamide dimethylacetal (DMF-DMA) (2), refluxing of 3 with ethyl acetoacetate (4) in a mixture of acetic acid and ammonium acetate afforded ethyl-6-(6-methoxynaphthalen2-yl)-2-methyl nicotinate (5), the condensation of 5 with hydrazine hydrate (6) resulted in the formation of 6-(6-methoxynaphthalen-2-yl)-2-methylnicotinohydrazide (7), which was adapted from the method reported previously [24]

Summary

Introduction

Nuclear receptors are important targets for drug development, which are related to the therapeutic effects of 16% of small molecule drugs [1]. Its natural ligand has not been discovered yet, it can be regulated by a variety of intracellular and extracellular stimuli and specific agonists/antagonists, and is involved in physiological regulation such as cell growth, differentiation, apoptosis, autophagy, metabolism, aging and immunity [2–6]. It has been found that Nur is a key participant and regulator in the occurrence and development of a variety of tumors [7], and it has abnormal expression in a variety of tumors, including liver cancer [8,9], prostate cancer [10] and colon cancer [11], and is closely related to tumor development, invasion and metastasis. Many agonists of Nur have been reported to have significant anticancer effects.

Methods

Results

Conclusion