Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo

Wang, Yang; Cheng, Fei; Yuan, Xiao Long; Tang, Wen; Shi, Jing; Liao, Chen; Liu, Xin Hua

doi:10.1016/j.ejmech.2016.02.009

Cited by 49 publications

(16 citation statements)

References 35 publications

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“…To gain a deeper understanding of the SAR of pyrazole‐based BRAF V600E inhibitors, we explored their interaction with BRAF V600E by molecular docking. Docking was based on the reported BRAF V600E /SB‐590885 complex structure (PDB code: 2FB8, obtained from the RCSB protein data bank, http://www.pdb.org) which was preprocessed by Discovery Studio (Accelrys, Inc., San Diego, CA) . Each ligand was docked as described previously, and the pose with the highest‐ECD (‐cdocker interaction energy) was considered as the optimal pose.…”

Section: Resultsmentioning

confidence: 99%

Modification, Biological Evaluation and SAR Studies of Novel 1H‐Pyrazol Derivatives Containing N,N′‐Disubstituted Urea Moiety as Potential Anti‐melanoma Agents

Ruan

Lin

Shao

et al. 2018

Chemistry & Biodiversity

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Malignant melanomas are amongst the most aggressive cancers. BRAF Inhibitors have exhibited therapeutic effects against BRAF-mutant melanoma. In continuation of our earlier studies on anti-melanoma agents based on 1H-pyrazole skeleton, two sets of novel compounds that include 1H-pyrazole-4-amines FA1 - FA13 and corresponding urea derivatives FN1 - FN13 have been synthesized and evaluated for their BRAF inhibitory and antiproliferation activities. Compound FN10 displayed the most potent biological activity against BRAF (IC = 0.066 μm) and the A375 human melanoma cell line (GI = 0.81 μm), which was comparable to the positive control vemurafenib, and more potent than our previously reported 1H-pyrazole-3-amines and their urea derivatives. The results of SAR studies and molecular docking can guide further optimization and may help to improve potency of these pyrazole-based anti-melanoma agents.

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Section: Resultsmentioning

confidence: 99%

Modification, Biological Evaluation and SAR Studies of Novel 1H‐Pyrazol Derivatives Containing N,N′‐Disubstituted Urea Moiety as Potential Anti‐melanoma Agents

Ruan

Lin

Shao

et al. 2018

Chemistry & Biodiversity

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“…Successful applications such as development of Bcl-2xL agents [80], topoisomerase I and II inhibitors [123], COX-2/5-LOX dual inhibitors [124], Rac1 agents [125], inhibitors of Hsp90 [126], inhibitors of Tip 60 [127], mTOR [128], histone deacetylase inhibitors [129], hTERT inhibitors [130,131] and CDK [29] agents highlight the importance of this virtual docking technique ( Table 2). These, like many other targets involved in cellular events such as cell growth, differentiation and proliferation, could serve as potential targets for drug discovery directed towards various types of cancer.…”

Section: Virtual Screening and Virtual Docking Methodsmentioning

confidence: 99%

“…Based on structure-based drug design, several series of compounds, including N-substituted-dihydropyrazoles, dihydropyrazole-coumarin and myricetin, were designed and synthesized as potential human telomerase inhibitors. The binding mode of these compounds was explored in docking studies which provide information that supports rational design of more efficient telomerase inhibitors [130,131].…”

Section: Virtual Screening and Virtual Docking Methodsmentioning

confidence: 99%

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

Vucicevic

Nikolić

Mitchell

2019

CMC

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Background: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Results: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. Conclusion: In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

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“…Among them, aryl‐2 H ‐pyrazoles containing 1,3‐benzodioxoles and electron‐donating aryl groups displayed considerable telomerase inhibition ( 12 , IC 50 = 0.9 μM); further, when N ‐acetyl was replaced by ethanethioamide, better potent inhibitory activity was observed ( 13 , IC 50 = 0.6 μM) . Such dihydropyrazole derivatives containing 2H‐chromen moiety showed anticancer activity against various cell lines and the most potent derivatives ( 14 ‐ 18 ) displayed strong telomerase inhibitory activity with IC 50 values of 0.8 to 2.0 μM (Figure ).…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

“…Among them, 2‐phenylchroman‐4‐one derivatives ( 15 ‐ 18 ) are the most important ones . Because they are effective in inhibiting dyskerin, they are thought to inhibit the interaction of dyskerin and NOP10 and reduce telomerase activity . More coumarin derivatives ( 37 ‐ 40 ) have been reported by other groups, and these structures are shown in Figure …”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Therapeutic strategies for targeting telomerase in cancer

Chen

Tang

Shi

et al. 2019

Medicinal Research Reviews

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Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

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Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo

Cited by 49 publications

References 35 publications

Modification, Biological Evaluation and SAR Studies of Novel 1H‐Pyrazol Derivatives Containing N,N′‐Disubstituted Urea Moiety as Potential Anti‐melanoma Agents

Modification, Biological Evaluation and SAR Studies of Novel 1H‐Pyrazol Derivatives Containing N,N′‐Disubstituted Urea Moiety as Potential Anti‐melanoma Agents

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

Therapeutic strategies for targeting telomerase in cancer

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