scholarly journals Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 321
Author(s):  
Farhana Islam ◽  
Arpit Doshi ◽  
Andrew J. Robles ◽  
Tasdique M. Quadery ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Biological Activities ◽  
Xenograft Model ◽  
Resistance Mechanisms ◽  
Biological Evaluation ◽  
Microtubule Depolymerization ◽  
Antitumor Effects ◽  
Design Synthesis ◽  
Microtubule Targeting Agents ◽  
Gewald Reaction ◽  
Ic50 Values

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

2020 ◽  
Vol 17 (11) ◽  
pp. 1330-1341
Author(s):  
Yan Zhang ◽  
Niefang Yu
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Gastric Cancer ◽  
Design Synthesis ◽  
Carbonyl Derivatives ◽  
Ic50 Values ◽  
Inhibitory Activities

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

scholarly journals Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 10 ◽  
Author(s):  
Hehua Xiong ◽  
Jianxin Cheng ◽  
Jianqing Zhang ◽  
Qian Zhang ◽  
Zhen Xiao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Docking Simulation ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Mcf 7

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

scholarly journals Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

2020 ◽  
Author(s):  
Laila Jarragh Alhadad ◽  
Fars Alanazi ◽  
Gamaleldin Harisa
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Biological Activities ◽  
Critical Role ◽  
Biological Evaluation ◽  
Crystallographic Analysis ◽  
Skbr3 Cell ◽  
Chemical Structures ◽  
Ic50 Values

Tubulin and heat shock protein 27 (HSP27) are up-regulated in cancer cells, and play a critical role in cell division, and proliferation. Therefore, they are targets for discovery of anticancer therapy. The objective of this study is to design, characterize, and biologically evaluate the nimesulide analogues to combat female cancer such as ovarian cancer, and breast cancer. Herein, the nimesulide analogues are designed to target both tubulin and HSP27 functions. Ovarian cancer (SKOV3) and breast cancer (SKBR3) cell lines were used as surrogate models to test the nimesulide analogs biological activities using MTT assay. In the present study, four nimesulide analogues were designed, synthesized and the chemical structures were with the biological evaluation were studied. The synthesized agents were characterized by 1H-NMR, 13C-NMR, the molecular weight was confirmed using GC-MS technique, and melting point. Besides, the agent L4 structure was confirmed using X-ray crystallographic analysis. The present data revealed that nimesulide analogs have potent anticancer activity against SKOV3and SKBR3 cell lines. The IC50 values for both SKOV3 and SKBR3 cell lines treated with the agents showed a potent cell growth inhibition range of 0.23-2.02 &micro;M and 0.50-3.73 &micro;M respectively. In conclusion, the designed nimesulide analogues can target both tubulins, and HSP27 concurrently, and they are promising agents as future chemotherapy female cancers.

Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents

2018 ◽  
Vol 144 ◽  
pp. 797-816 ◽  
Author(s):  
Tomasz Stefański ◽  
Renata Mikstacka ◽  
Rafał Kurczab ◽  
Zbigniew Dutkiewicz ◽  
Małgorzata Kucińska ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Design Synthesis ◽  
Microtubule Targeting Agents ◽  
Synthesis And Biological Evaluation

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (03) ◽  
pp. e143-e149
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (02) ◽  
pp. e117-e123
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3327
Author(s):  
Ziad Omran ◽  
Chris P. Guise ◽  
Linwei Chen ◽  
Cyril Rauch ◽  
Ashraf N. Abdalla ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Biological Activities ◽  
Multidrug Resistant ◽  
Biological Evaluation ◽  
High Chemical ◽  
Design Synthesis ◽  
Hypoxic Conditions ◽  
Cancerous Cell

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

scholarly journals Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors

2021 ◽  
Vol 22 (8) ◽  
pp. 4145
Author(s):  
Daniela Malafaia ◽  
Ana Oliveira ◽  
Pedro A. Fernandes ◽  
Maria J. Ramos ◽  
Hélio M. T. Albuquerque ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Biological Evaluation ◽  
Catalytic Triad ◽  
Related Factors ◽  
Design Synthesis ◽  
Aβ Aggregation ◽  
Ic50 Values ◽  
The Central Nervous System ◽  
Dual Inhibitors ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is a complex multifactorial disorder, mainly characterized by the progressive loss of memory and cognitive, motor, and functional capacity. The absence of effective therapies available for AD alongside the consecutive failures in the central nervous system (CNS) drug development has been motivating the search for new disease-modifying therapeutic strategies for this disease. To address this issue, the multitarget directed ligands (MTDLs) are emerging as a therapeutic alternative to target the multiple AD-related factors. Following this concept, herein we describe the design, synthesis, and biological evaluation of a family of chromeno[3,4-b]xanthones as well as their (E)-2-[2-(propargyloxy)styryl]chromone precursors, as first-in-class acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation dual-inhibitors. Compounds 4b and 10 emerged as well-balanced dual-target inhibitors, with IC50 values of 3.9 and 2.9 μM for AChE and inhibitory percentages of 70 and 66% for Aβ aggregation, respectively. The molecular docking showed that most of the compounds bound to AChE through hydrogen bonds with residues of the catalytic triad and π-stacking interactions between the main scaffold and the aromatic residues present in the binding pocket. The interesting well-balanced activities of these compounds makes them interesting templates for the development of new multitarget compounds for AD.

scholarly journals Design, Synthesis and Biological Evaluation of Aromatase Inhibitors based on Sulfonates and Sulfonamides of Resveratrol

2021 ◽  
Vol 14 (10) ◽  
pp. 984
Author(s):  
Marialuigia Fantacuzzi ◽  
Marialucia Gallorini ◽  
Nicola Gambacorta ◽  
Alessandra Ammazzalorso ◽  
Zeineb Aturki ◽  
...  
Keyword(s):  
Aromatase Inhibitors ◽  
Biological Response ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Mcf7 Cell Line ◽  
Nano Liquid Chromatography ◽  
Inhibitory Potential

A library of sulfonate and sulfonamide derivatives of Resveratrol was synthesized and tested for its aromatase inhibitory potential. Interestingly, sulfonate derivatives were found to be more active than sulfonamide bioisosteres with IC50 values in the low micromolar range. The sulfonate analogues 1b–c and 1j exhibited good in vitro antiproliferative activity on the MCF7 cell line, evidenced by MTT and LDH release assays. Structure–activity relationships suggested that electronic and lipophilic properties could have a different role in promoting the biological response for sulfonates and sulfonamides, respectively. Docking studies disclosed the main interactions at a molecular level of detail behind the observed inhibition of the more active compounds whose chemical stability has been evaluated with nano-liquid chromatography. Finally, 1b–c and 1j were highlighted as sulfonates to be further developed as novel and original aromatase inhibitors.

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