Design, synthesis and biological evaluation of novel 5,6,7-trimethoxy-N-aryl-2-styrylquinolin-4-amines as potential anticancer agents and tubulin polymerization inhibitors

Mirzaei, Salimeh; Eisvand, Farhad; Hadizadeh, Farzin; Mosaffa, Fatemeh; Ghasemi, Ali; Ghodsi, Razieh

doi:10.1016/j.bioorg.2020.103711

Cited by 60 publications

(55 citation statements)

References 41 publications

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“…The α - and β -tubulin heterodimers are in dynamic equilibrium with microtubules. The impairment of the dynamic equilibrium of microtubules leads to mitotic arrest and accordingly apoptosis [ 7 , 8 ]. Therefore, microtubule targeting agents that interfere with dynamic microtubules can be effective in the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

“…However, the use of these agents is limited due to drug resistance and associated side effects [ 16 , 17 ]. Recently, different small molecules have been designed as tubulin inhibitors and anticancer agents [ 5 , 8 , 12 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this paper, quinolines with cytotoxic activities were used to develop new potent anticancer agents. We selected some cytotoxic quinolines (1-62) as tubulin inhibitors from our previous works [ 5 , 8 ], generated a training set and test set, and created 279 pharmacophore models with activity prediction ability. Then, we screened the database based on the best pharmacophore model and docked the selected compounds into the colchicine binding site of tubulin.…”

Section: Introductionmentioning

confidence: 99%

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3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity

Mirzaei

Ghodsi

Hadizadeh

et al. 2021

BioMed Research International

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In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient ( R 2 = 0.865 ), cross-validation coefficient ( Q 2 = 0.718 ), and F value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity

Mirzaei

Ghodsi

Hadizadeh

et al. 2021

BioMed Research International

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“…We assembled a dataset of 851 compounds tested as Tub-Mts inhibitors and with reported bioactivity in different cancer cell lines [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. All compounds were retrieved from original and review articles and patents over a period of 15 years (2005–2020).…”

Section: Methodsmentioning

confidence: 99%

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

2021

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Inhibiting the tubulin-microtubules (Tub-Mts) system is a classic and rational approach for treating different types of cancers. A large amount of data on inhibitors in the clinic supports Tub-Mts as a validated target. However, most of the inhibitors reported thus far have been developed around common chemical scaffolds covering a narrow region of the chemical space with limited innovation. This manuscript aims to discuss the first activity landscape and scaffold content analysis of an assembled and curated cell-based database of 851 Tub-Mts inhibitors with reported activity against five cancer cell lines and the Tub-Mts system. The structure–bioactivity relationships of the Tub-Mts system inhibitors were further explored using constellations plots. This recently developed methodology enables the rapid but quantitative assessment of analog series enriched with active compounds. The constellations plots identified promising analog series with high average biological activity that could be the starting points of new and more potent Tub-Mts inhibitors.

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“…Over the last few years, numbers of pyrimidine-containing drugs have been approved for clinical use, such as Imatinib (anticancer), Macitentan (antihypertensive), and Ceritinib (anticancer) (Figure 1) 21,22) . Besides At present, molecular hybrid-based approach is a useful tool for the design of new tubulin inhibitors 26,27) . Based on these findings and in continuation of our search novel tubulin polymerization inhibitors 28,29) , we designed the synthesis of a novel series of 4-(4-methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines (5a-5s) and further evaluated for their antiproliferative and tubulin polymerization inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel 4-(4-Methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines as Tubulin Polymerization Inhibitors

Liu

Wang

Peng

et al. 2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of 4-(4-methoxynaphthalen-1-yl)-5-arylpyrimidin-2amines were designed, synthesized, and evaluated for their anticancer activities. Most of the synthesized compounds exhibited moderate to high antiproliferative activity in comparison to the standard drug cisplatin. Among them, 5i bearing ethoxy at the 4-position of the phenyl was found to be the most active on MCF-7 and HepG2 cancer cell lines, with IC 50 values of 3.77±0.36 μM and 3.83±0.26, respectively. Further mechanism study shown that 5i potently inhibited tubulin polymerization, induced cell cycle arrest at G2/M phase and cell apoptosis in MCF-7 cell line. Furthermore, molecular modeling study suggested that 5i probably binds to the colchicine site of tubulin.

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Design, synthesis and biological evaluation of novel 5,6,7-trimethoxy-N-aryl-2-styrylquinolin-4-amines as potential anticancer agents and tubulin polymerization inhibitors

Cited by 60 publications

References 41 publications

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

Design, Synthesis and Biological Evaluation of Novel 4-(4-Methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines as Tubulin Polymerization Inhibitors

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