Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells

He, Zhang-Xu; Huo, Jin-Ling; Gong, Yunpeng; An, Q.; Zhang, Xin; Qiao, Hui; Yang, Feifei; Zhang, Xinhui; Jiao, Le-Min; Liu, Hong‐Min; Ma, Liying; Zhao, Wen

doi:10.1016/j.ejmech.2020.112970

Cited by 24 publications

(10 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notable medicinal applications associated with the quinoline heterocycle include anticancer, anti-tubercular, antiproliferative, anti-malarial, antibacterial, anti-inflammatory, anti-protozoal, anti-fungal, anti-tumor, antioxidant, anti-HIV, anti-hypertensive, alkaline phosphatase inhibition and for the treatment of neurodegenerative disorders [19][20][21][22][23][24][25][26][27][28]. In parallel, thiosemicarbazones also display a wide plethora of biological properties ranging from anticancer, anti-bacterial, anti-tumor, anti-protozoal, anti-fungal, anti-leishmanial, and antiviral activities [29][30][31][32][33][34]. Thiosemicarbazone derivatives have also been employed as NDRG1 up-regulators, cathepsin inhibitors, and cholinesterase inhibitors for the treatment of Alzheimer's disease [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…According to the SI results, most of the compounds exhibited SI values below 1, with the exception of 2a , 6a , 6b , 6c , 6d , and 6e in breast cancer, and only 6d in lung cancer. Remarkably, the most effective analog ( 6c ) presents similar or slightly better cytotoxic activity than many of the most recent urea [ 43 ] and thiourea [ 44 ] derivatives reported, showing much greater antitumor effects than several thiosemicarbazone derivatives recently published in relation to MCF-7 cells [ 45 , 46 ].…”

Section: Resultsmentioning

confidence: 92%

Novel N,N′-Disubstituted Selenoureas as Potential Antioxidant and Cytotoxic Agents

et al. 2021

View full text Add to dashboard Cite

A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was tested in vitro in a panel of three different cancer (breast, lung and colon) and two normal cell lines. Each selenourea entity contains a para-substituted phenyl ring with different electron-withdrawing and electron-donating groups, and different aliphatic and aromatic nuclei. All of the synthesized selenoureas present antioxidant capacity at high concentrations in the DPPH assay, and three of them (2b, 2c and 2d) showed greater radical scavenging capacity than ascorbic acid at lower concentrations. These results were confirmed by the ABTS assay, where these novel selenoureas present even higher antioxidant capacity than the reference compound Trolox. On the other hand, 10 selenoureas present IC50 values below 10 µM in at least one cancer cell line, resulting in the adamantyl nucleus (6a–6e), the most interesting in terms of activity and selectivity. Outstanding results were found for selenourea 6c, tested in the NCI60 cell line panel and showing an average GI50 of 1.49 µM for the 60 cell lines, and LC50 values ranging from 9.33 µM to 4.27 µM against 10 of these cancer cell lines. To gain insight into its anticancer activity mechanism, we investigated the cell cycle progression of the promising compound 6c, as well as the type of programmed-cell death in a colon cancer cell line it provokes (HT-29). Compound 6c provoked S phase cell cycle arrest and the induction of cell death was independent of caspase activation, suggesting autophagy, though this assertion requires additional studies. Overall, we envision that this compound can be further developed for the potential treatment of colon cancer.

show abstract

“…This indicates the ability of 3-methyleneisoindolinone to disturb the cell cycle process, which was in consonance with previous findings of a similar category of anticancer compounds. 31 , 35 , 36 However, it was interesting to find that all the three leads arrest the cell cycle in different phases and could have a different mode of action on cancer cells. Additionally, a dose-dependent increase in the percentage of the cell population was observed in the Sub-G1 phase for 3n and 3h , indicating the presence of cellular apoptosis ( Figure 7 c,e).…”

Section: Resultsmentioning

confidence: 99%

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

et al. 2022

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world and the most prevalent cancer of developing countries. Increased disease burden and a smaller number of approved targeted therapies are a growing concern worldwide. Isoindolinone motifs have been a central part of many pharmacological compounds, and their derivatives possess substantial anticancer potential. However, their anticancer potential against HNSCC has not been well investigated. In the current study, a series of 3-methyleneisoindolinones have been designed and synthesized and their late-stage intramolecular Heck cyclization was achieved to evaluate their anticancer potential against HNSCC cells. Additionally, in silico ADME profiling of synthesized compounds revealed their drug-likeness properties as potential drug candidates. Among the synthesized compounds, 3-bromo-5-methylpyridin-2-yl-3-methyleneisoindolin-1-one, i.e., 3n, with a pyridyl unit exhibited the most significant cytotoxicity against HNSCC cells. The cytotoxic potential of synthesized compounds varied depending on the nature of substituents present and has been well established with structure–activity relationship studies. Further, flow cytometric analysis showed that 3f, 3h, and 3n triggered intracellular oxidative stress, disrupted mitochondrial membrane potential, and interrupted the cell cycle of HNSCC cells in the S-phase and sub-G1 phase. Further, 3f, 3h, and 3n also exhibited pro-apoptotic potential and induced cellular apoptosis in the HNSCC cells. Overall, the findings of this study attributed 3-methyleneisoindolinone chemistry and efficacy evaluation and corroborated their anticancer potential against HNSCC. It will pave the way to further design and optimize novel 3-methyleneisoindolinone as effective antitumor agents, which may provide effective treatment modalities against HNSCC.

show abstract

Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells

Cited by 24 publications

References 48 publications

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Novel N,N′-Disubstituted Selenoureas as Potential Antioxidant and Cytotoxic Agents

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

Contact Info

Product

Resources

About