Design, synthesis and biological evaluation of substituted aminopyridazin-3(2 H )-ones as G0/G1-phase arresting agents with apoptosis-inducing activities

Ge, Bing-Chen; Feng, Hong-Fang; Cheng, Yufang; Wang, Haitao; Xi, Bao-Ming; Yang, Xuemei; Zhou, Zhong‐Zhen

doi:10.1016/j.ejmech.2017.09.077

Cited by 11 publications

(4 citation statements)

References 21 publications

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“…Our recent research was mainly focused on potential heterocyclic anticancer agents based on different kinds of heterocyclic scaffolds. − Our reported compounds 4 and 5 with purine bridging group displayed promising antitumor activities and lower cytotoxicity in normal cells but weak tubulin polymerization inhibition activity . Nevertheless, the potent biological profile encouraged us to continue our search for high-potency antitumor drugs.…”

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confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Zhang

Tang

et al. 2020

ACS Med. Chem. Lett.

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Mimicking different pharmacophoric units into one scaffold is a promising structural modification tool to design new drugs with enhanced biological properties. To continue our research on the tubulin inhibitors, the synthesis and biological evaluation of arylpyridine derivatives (9−29) are described herein. Among these compounds, 6-arylpyridines (13−23) bearing benzo[d]imidazole side chains at the 2-position of pyridine ring displayed selective antiproliferative activities against HT-29 cells. More interestingly, 2-trimethoxyphenylpyridines 25, 27, and 29 bearing benzo[d]imidazole and benzo[d]oxazole side chains displayed more broad-spectrum antitumor activities against all tested cancer cell lines. 29 bearing a 6-methoxybenzo[d]oxazole group exhibited comparable activities against A549 and U251 cells to combretastatin A-4 (CA-4) and lower cytotoxicities than CA-4 and 5-Fu. Further investigations revealed 29 displays strong tubulin polymerization inhibitory activity (IC 50 = 2.1 μM) and effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network.

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confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Zhang

Tang

et al. 2020

ACS Med. Chem. Lett.

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“…These assays were carried out as our previously reported methods (Ge et al., ; Zhou et al., , , ). These compounds were diluted in 10% DMSO and 5 μl of the dilution was added to a 50 μl reaction mixture, which is comprised of 40 mM MOPS, pH 7.5, 0.5 mM EDTA, 15 mM MgCl 2 , 0.15 mg/ml BSA, 1 mM DTT, 0.05% Proclin 200, 15 ng/ml PDE4CAT, and 100 nM FAM‐Cyclic‐3′,5′‐AMP.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have devoted ourselves to the discovery of new selective PDE4 inhibitors with potential for CNS disorders and reported several series of PDE4 inhibitors (Ge et al., ; Zhou et al., , , ), such as FCPE07 (8), FCPR16 (9), and FCPR03 (10). Among these compounds (Figure ), FCPR03 (Zhou et al., ; Zou et al., ) and FCPR16 (Zhou et al., ) with selective PDE4 inhibitory activities displayed good anti‐neuroinflammation activities.…”

Section: Introductionmentioning

confidence: 99%

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

et al. 2018

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Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q2), conventional coefficient (r2), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC50 values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.

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“…Compound IV exhibits potent activity against breast cancer cells, arresting cells in the G0/G1-phase and decreasing the cellular levels of cyclin D1. 5 G0/G1-phase arresting agents V (6) and VI (7) show good anticancer activity against SH-SY5Y cells and HCT-116 colon cancer cells, respectively.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Dihydropyrrol-2-ones as Novel G0/G1-Phase Arresting Agents Inducing Apoptosis

et al. 2019

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A series of dihydropyrrol-2-ones (DHPs) were designed and synthesized via an efficient multicomponent reaction at room temperature for evaluation of their bioactivities against four human cancer lines (MCF-7, RKO, HeLa, and A549) in vitro. Preliminary structure–activity relationship studies showed that R4 = 3-MeO-4-OH-Ph is a crucial group for increasing cytotoxicities against RKO cells and the influences of R1–R3 depend on their combination. It was found that DHPs 5a, 5q, and 5s showed the best antiproliferative activities against A549, RKO, and all four studied cell lines, respectively (IC50 = 1.9, 0.8, and 0.9–2.4 μM). They can be used as new lead compounds for developing potentially selective or broad spectrum anticancer agents. 5q proves as a potent G0/G1-phase arresting agent inducing cell apoptosis by increasing/decreasing the levels of p53 and p21/cyclin D1.

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Design, synthesis and biological evaluation of substituted aminopyridazin-3(2 H )-ones as G0/G1-phase arresting agents with apoptosis-inducing activities

Cited by 11 publications

References 21 publications

Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Discovery of Dihydropyrrol-2-ones as Novel G0/G1-Phase Arresting Agents Inducing Apoptosis

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