Design, Synthesis and Evaluation of Naphthalimide Derivatives as Potential Anticancer Agents for Hepatocellular Carcinoma

Ge, Chaochao; Chang, Liping; Zhao, Ying; Chang, Cong-Cong; Xu, Xiaojuan; He, Haoying; Wang, Yuxia; Dai, Fujun; Xie, Songqiang; Wang, Chaojie

doi:10.3390/molecules22020342

Cited by 19 publications

(7 citation statements)

References 42 publications

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“…Naphthalimide compounds are DNA intercalators that can insert into the middle of a base pair, causing changes in the topology of the DNA, and thus affecting topoisomerase function and recognition of DNA (8,16). The naphthalimide derivatives, including amonafide (17), mitonafide (18) and UNBS5162 (19), remain in clinical research. However, in clinical trials, mitonafide and amonafide exhibited marked side effects on the central nervous system, leading to thrombocytopenia, anaemia and leukopenia, and thus these two drugs failed to enter Phase III clinical trials (20).…”

Section: Discussionmentioning

confidence: 99%

UNBS5162 inhibits SKOV3 ovarian cancer cell proliferation by regulating the PI3K/AKT signalling pathway

Wang

Wei

2019

Oncol Lett

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Ovarian cancer is the gynaecological malignancy with the highest mortality rate worldwide, and effective and safe therapeutic methods are limited. UNBS5162, a derivative of naphthalimide, has a clear inhibitory effect on the proliferation of various tumour cells in vitro and in vivo as a pan-antagonist of CXC chemokine ligand expression, but whether it serves a function in ovarian cancer remains unclear. The aim of the present study was to determine the effects of UNBS5162 on the proliferation, migration and invasion of ovarian cancer cells. The cell viability was detected using a Cell Counting Kit-8 (CCK-8) assay. The invasion and migration of SKOV3 cells were determined using Transwell assays. Cell apoptosis was determined using flow cytometry. The apoptosis-associated proteins and associated factors, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway members, were detected using western blot analysis. The CCK-8 assay revealed that SKOV3 cell viability was affected by UNBS5162 in a dose-and time-dependent manner. In Transwell assays, UNBS5162 inhibited cell invasion and migration. Furthermore, it was identified that UNBS5162 markedly increased the apoptosis rate of SKOV3 cells. Simultaneously, the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) was decreased and the expression of the pro-apoptotic proteins active caspase-3 and Bcl-2-associated X protein were increased in SKOV3 cells treated with UNBS5162. In addition, the expression levels of phospho (p-)AKT/total AKT, p-mammalian target of rapamycin (mTOR)/total mTOR, p-p70 S6 kinase (p70S6K)/total p70S6K and cyclin D1 were decreased in the UNBS5162-treated group. The results of the present study indicated that UNBS5162 inhibits proliferation, migration and invasion, and induces apoptosis in ovarian cancer cells, which may be regulated by the PI3K/AKT signalling pathway. These results suggest that UNBS5162 may be a potential novel drug for clinical ovarian cancer treatment.

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Section: Discussionmentioning

confidence: 99%

UNBS5162 inhibits SKOV3 ovarian cancer cell proliferation by regulating the PI3K/AKT signalling pathway

Wang

Wei

2019

Oncol Lett

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“…Naphthalimides, which are DNA intercalators, have been investigated extensively as antitumor agents (24). Among antitumor agents, naphthalimide analog derivatives are among the most promising classes of anticancer drug candidates (25)(26)(27). Amonafide, elinafide and mitonafide have reached the clinical trials stage for the treatment of various tumors and exhibited excellent antitumor activity, however, the majority were abandoned due to severe adverse effects such as dose-limiting or bone marrow toxicity (28).…”

Section: Discussionmentioning

confidence: 99%

UNBS5162 inhibits the proliferation of esophageal cancer squamous cells via the PI3K/AKT signaling pathway

Zhang

2017

Mol Med Report

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C‑X‑C motif chemokine ligand (CXCL) signaling has been demonstrated to be involved in cancer invasion and migration; therefore, CXCL antagonists may serve as anticancer drugs by preventing tumor proliferation. The present study aimed to investigate whether a pan antagonist of CXCLs, UNBS5162, may inhibit esophageal cancer proliferation and to identify the underlying mechanisms. Cell proliferation and cell colony formation results, which were determined by a Cell Counting Kit‑8 assay and crystal violet staining, respectively, demonstrated that UNBS5162 inhibited esophageal cancer cell proliferation. Following treatment with UNBS5162, Transwell migration and Matrigel invasion assays, and flow cytometry with Annexin V‑fluorescein isothiocyanate and propidium iodide staining, were performed to investigate cell migration, invasion and apoptosis in human esophageal cancer cells. The results indicated that invasion and migration was reduced in UNBS5162‑treated cells, while apoptosis was increased. Western blotting experiments confirmed that UNBS5162 downregulated the protein expression of proteins associated with the phosphatidylinositol 3‑kinase (PI3K)/AKT signaling pathway, including the levels of phosphorylated (p)‑AKT, p‑mechanistic target of rapamycin kinase, ribosomal protein S6 kinase β1 and cyclin D1. In addition, upregulated expression of programed cell death 4 was observed following UNBS5162 treatment. The present study demonstrated that UNBS5162 is a novel naphthalimide that may have potential therapeutic use for the prevention of esophageal cancer proliferation and metastasis via the PI3K/AKT signaling pathway.

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“…In 2017, GE Chaochao et al 39 designed a class of compounds with fused thiazole rings ( Figure 13 ), in which the IC 50 values of 26a and 26c on human hepatoma cells (SMMC7721 and HepG2) were 1 to 10 μM range. The metastasis and diffusion of cancer cells is one of the main reasons why it is difficult to cure.…”

Section: Studies On Other Naphthalimide Derivativesmentioning

confidence: 99%

Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor

Zhang,

Han,

et al. 2024

Technol Cancer Res Treat

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The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

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Design, Synthesis and Evaluation of Naphthalimide Derivatives as Potential Anticancer Agents for Hepatocellular Carcinoma

Cited by 19 publications

References 42 publications

UNBS5162 inhibits SKOV3 ovarian cancer cell proliferation by regulating the PI3K/AKT signalling pathway

UNBS5162 inhibits SKOV3 ovarian cancer cell proliferation by regulating the PI3K/AKT signalling pathway

UNBS5162 inhibits the proliferation of esophageal cancer squamous cells via the PI3K/AKT signaling pathway

Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor

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