Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells

Sbenati, Rawan M.; Zaraei, Seyed–Omar; El–Gamal, Mohammed I.; Anbar, Hanan S.; Tarazi, Hamadeh; Zoghbor, Malaka M.; Mohamood, Najma A.; Khakpour, Mahta M; Zaher, Dana M.; Omar, Hany A.; Alach, Nour N.; Shehata, Mahmoud K.; El-Gamal, Randa

doi:10.1016/j.ejmech.2020.113081

Cited by 14 publications

(7 citation statements)

References 28 publications

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“…These factors may be responsible for cancer-related mutations, DNA damage, and epigenetic alterations, resulting in inactivated oncogenes or inactivated tumor suppressor genes, ultimately leading to HCC development ( Rovida et al, 2015 ; Ally et al, 2017 ; Dang et al, 2017 ). Current treatment strategies for HCC include specific kinase inhibitors, anti-hepatitis vaccine, and liver resection and transplantation ( Dageforde et al, 2021 ; Pattyn et al, 2021 ; Sbenati et al, 2021 ; Yamamoto et al, 2021 ). These therapeutic approaches in combination with biomarker screening reduce HCC-related death.…”

Section: Introductionmentioning

confidence: 99%

Mapping Intellectual Structure for the Long Non-Coding RNA in Hepatocellular Carcinoma Development Research

Lin

Tian

et al. 2022

Front. Genet.

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Background: Emerging research suggests that long non-coding RNAs (lncRNAs) play an important role in a variety of developmental or physiological processes of hepatocellular carcinoma (HCC). Various differentially expressed lncRNAs have been identified in HCC. Thus, a deeper analysis of recent research concerning lncRNA and HCC development could provide scientists with a valuable reference for future studies.Methods: Related publications were retrieved from the Web of Science Core Collection database. CiteSpace version 5.6.R4 was employed to conduct bibliometric analysis. Several network maps were constructed to evaluate the collaborations between different countries, institutions, authors, journals, and keywords.Results: A total of 2,667 records were initially found from the year of 2010–2020. The annual related publications output had increased dramatically during these years. Although China was the most prolific country in terms of research publication, the United States played a leading role in collaborative network. The Nanjing Medical University was the most productive institute in the field of lncRNAs in HCC development. Gang Chen was the most prolific researcher, while Yang F was the most frequently co-cited author. Oncotarget, Cell, and Oncogene were the most highly co-cited journals. The most recent burst keywords were interaction, database, and pathway.Conclusion: This study provides a comprehensive overview for the field of lncRNAs in HCC development based on bibliometric and visualized methods. The results would provide a reference for scholars focusing on this field.

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Section: Introductionmentioning

confidence: 99%

Mapping Intellectual Structure for the Long Non-Coding RNA in Hepatocellular Carcinoma Development Research

Lin

Tian

et al. 2022

Front. Genet.

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“…In clinical practice, multi-target tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF) could inhibit the growth and development of HCC by suppressing angiogenesis. However, these drugs still have limitations [ 4 – 6 ]. Therefore, it is vital to explore new targets for the treatment of HCC by regulating HCC angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma

Zhu

Chen

Feng

et al. 2021

J Exp Clin Cancer Res

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Background Angiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). According to previous studies, miR-378a participates in tumorigenesis and tumor metastasis, but its exact role in HCC angiogenesis remains poorly understood. Methods qRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by Cell Counting Kit-8 (CCK-8), Transwell, tube formation and Matrigel plug assays, RNA sequencing, bioinformatics, luciferase reporter, immunofluorescence and chromatin immunoprecipitation (ChIP) assays were used to detect the molecular mechanism by which miR-378a-3p inhibits angiogenesis. Results We confirmed that miR-378a-3p expression was significantly downregulated and associated with higher microvascular density (MVD) in HCC; miR-378a-3p downregulation indicated a short survival time in HCC patients. miR-378a-3p knockdown led to a significant increase in angiogenesis in vitro and in vivo. We found that miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then downregulated secreted vascular endothelial growth factor. DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of miR-378a-3p was responsible for downregulating miR-378a-3p. Moreover, a series of investigations indicated that p65 initiated a positive feedback loop that could upregulate DNMT1 to promote hypermethylation of the miR-378a-3p promoter. Conclusion Our study indicates a novel DNMT1/miR-378a-3p/TRAF1/NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.

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“…The representative diarylurea endowed with both CF 3 /OCF 3 substituents has recently been developed as an inhibitor of the most lethal and aggressive subtype of breast cancer [25]. Selective kinase inhibitory agents towards hepatocellular carcinoma cells were found among a series of conformationally restricted fluorinated ureas, analogues of sorafenib [26].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

et al. 2021

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Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC50 ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF3-phenyl (8) substituents displayed the highest activity (IC50 from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1–3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20–93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45–58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95–99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23–63%.

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Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells

Cited by 14 publications

References 28 publications

Mapping Intellectual Structure for the Long Non-Coding RNA in Hepatocellular Carcinoma Development Research

Mapping Intellectual Structure for the Long Non-Coding RNA in Hepatocellular Carcinoma Development Research

DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma

Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

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