scholarly journals DESIGN AND ANTICANCER ACTIVITY PREDICTION OF DIHYROPYRIMIDINONE BASED NOVEL INHIBITORS OF P53-MDM2 INTERACTION

2017 ◽  
Vol 10 (16) ◽  
pp. 110
Author(s):  
Surendra Kumar Nayak ◽  
Gopal Lal Khatik ◽  
Rakesh Narang ◽  
Harish Kumar Chopra
Keyword(s):  
Anticancer Activity ◽  
Binding Affinity ◽  
Anticancer Agents ◽  
P53 Protein ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Activity Prediction ◽  
Cycle Regulation ◽  
Mdm2 Inhibitor ◽  
Better Than

  Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using “Cancer IN” server.Methods: In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC50, anticancer activity, and toxicity profile were designed. Lead L11 was obtained after sequential isosteric replacement of functional groups for optimization in compound L0.Results: The docking scores of L3-L11 found to be in range of 21-25 close to docking score 25 of SAR405838 and better than nutlin-3a. MDM2 binding affinity values (37-78 Kcal/mol) of all ligands were also found to better than that of nutlin-3a (37 Kcal/mol). Surprisingly, MDM2 binding affinity of L11 (78 Kcal/mol) found to be equal to that of SAR405838 and 2-fold greater than nutlin-3a.Conclusion: These data indicating that L11 as a potential lead from dihydropyrimidinones for inhibition of p53-MDM2 interaction.

scholarly journals IDENTIFICATION OF NOVEL 5-STYRYL-1,2,4-OXADIAZOLE/TRIAZOLE DERIVATIVES AS THE POTENTIAL ANTI-ANDROGENS THROUGH MOLECULAR DOCKING STUDY

2016 ◽  
Vol 8 (10) ◽  
pp. 72 ◽  
Author(s):  
Paranjeet Kaur ◽  
Gopal L. Khatik
Keyword(s):  
Molecular Docking ◽  
Androgen Receptor ◽  
Binding Affinity ◽  
Docking Study ◽  
Molecular Structures ◽  
The Novel ◽  
Autodock Vina ◽  
Molecular Docking Study ◽  
Triazole Derivatives ◽  
Better Than

<p class="Default"><strong>Objective: </strong>To identify the novel and simple bioactive antiandrogens, that can overcome to side effects as well as drug resistance.</p><p class="Default"><strong>Methods: </strong>The AutoDock Vina (ADT) 1.5.6 software is used for molecular docking purposes. The molecular structures were drawn in ChemBiodraw ultra and by the help of ChemBiodraw 3D, all structures were energy minimized by MM2 method and converted to pdb extension file which is readable at the ADT interface.</p><p class="Default"><strong>Results: </strong>Total ten compounds from both series were shown better binding affinity than <em>R</em>-bicalutamide including oxadiazole and triazole series. Among these pk42 and pk46 were studied in-depth which showed best binding affinity to the androgen receptor. The <em>cis</em>-isomers were found better than their <em>trans</em>-isomer.</p><p><strong>Conclusion: </strong>Novel 5-styryl-1,2,4-oxadiazole/triazole derivatives were studied through molecular modeling using Autodock Vina. The potent compounds which showed better binding affinity than <em>R</em>-bicalutamide like pk24 and 46 were further analyzed for their interactions. The conformational effect also found significant in binding to the androgen receptor.</p>

Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity

2019 ◽  
Vol 19 (3) ◽  
pp. 310-322
Author(s):  
Amany S. Mostafa ◽  
Waleed A. Bayoumi ◽  
Mohamed El-Mesery ◽  
Abdelaziz Elgaml
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Molecular Design ◽  
Growth Factor Receptor ◽  
Docking Study ◽  
Structural Features ◽  
Significant Activity ◽  
Inhibiting Activity ◽  
Molecular Docking Study

Background: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity. Methods: All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay. Results: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively. Conclusion: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.

Discovery of a Highly Potent and Novel Gambogic Acid Derivative as an Anticancer Drug Candidate

2020 ◽  
Vol 20 ◽  
Author(s):  
Huiping Ling ◽  
Hong Li ◽  
Meijun Chen ◽  
Baolong Lai ◽  
Haiming Zhou ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Anticancer Agents ◽  
Docking Study ◽  
Gambogic Acid ◽  
Drug Candidate ◽  
Molecular Docking Study ◽  
Discovery Studio ◽  
Mcf 7

Background and Purpose: Gambogic acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anticancer agents. Methods: Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Antitumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye were used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKβ was studied by using Discovery Studio 2016. Results: Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with IC50 value of 1.49 ± 0.11, 1.37 ± 0.06 and 0.64 ± 0.16μM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKβ and compound 4, compared with GA. Conclusion: Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA’s binding affinity to IKKβ. Compound 4 may serve as a potential lead compound for the development of new anticancer drugs.

Design, synthesis and structure-activity relationship studies of novel spirochromanone hydrochloride analogs as anticancer agents

2022 ◽  
Author(s):  
Surendar Chitti ◽  
Sravani Pulya ◽  
Adinarayana Nandikolla ◽  
Tarun Kumar Patel ◽  
Karan Kumar Banoth ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Growth Factor Receptor ◽  
Docking Study ◽  
Kinase Domain ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Hek 293 ◽  
B16f10 Cells ◽  
Mcf 7

Aim: Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1–18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31 μm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and ∼ two/∼four fold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.

Synthesis, Antimicrobial Evaluation and Docking Study of Novel Thiosemicarbazone clubbed with 1,2,3-Triazoles

2020 ◽  
Vol 16 ◽  
Author(s):  
Adinath D. Badar ◽  
Shubham M. Sulakhe ◽  
Mahesh B. Muluk ◽  
Naziya N. M. A. Rehman ◽  
Prashant P. Dixit ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Biological Activities ◽  
Dna Gyrase ◽  
Docking Study ◽  
Antimicrobial Activities ◽  
Diffusion Method ◽  
Molecular Docking Study ◽  
Triazole Derivatives ◽  
Antibacterial And Antifungal

Background: Thiosemicarbazone, 1,2,3-triazole and their derivatives received great pharmaceutical importance due to their prominent biological activities. In the present study, the molecular hybrid thiosemicarbazone-1,2,3-triazoles derivatives were synthesized and screened for their antimicrobial activities. Methods: A series of thiosemicarbazone clubbed with 1,2,3-triazole derivatives were synthesized via click chemistry approach in good yields. The structures of synthesized compounds were assigned by their spectral data. The in vitro antimicrobial activity was performed by the agar well diffusion method. A molecular docking study was performed to identify the possible mode of action of synthesized derivatives. Results: The compounds 5d, 5h, 5i and 5k have exhibited excellent antimicrobial activities against both antibacterial and antifungal pathogens. The active thiosemicarbazone-1,2,3-triazole derivatives have shown excellent binding affinity towards DNA gyrase. Conclusion: The molecular hybrid thiosemicarbazone-1,2,3-triazole derivatives were synthesized. The newly synthesized compounds were evaluated for their antimicrobial activities. Few of the thiosemicarbazone-1,2,3-triazoles derivatives have exhibited good antimicrobial activities. They have been shown excellent binding affinity towards DNA gyrase.

scholarly journals Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1790
Author(s):  
Katarzyna Malarz ◽  
Jacek Mularski ◽  
Michał Kuczak ◽  
Anna Mrozek-Wilczkiewicz ◽  
Robert Musiol
Keyword(s):  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
P53 Protein ◽  
Structural Similarity ◽  
M Cell ◽  
Cycle Arrest ◽  
Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

scholarly journals Synthesis and Anticancer Activity Evaluation of Azepinobisindoles; the Isomeric Iheyamine A Derivatives

2019 ◽  
Vol 35 (2) ◽  
pp. 723-731
Author(s):  
Weerachai Phutdhawong ◽  
Sopita Rattanopas ◽  
Jitnapa Sirirak ◽  
Thongchai Taechowisan ◽  
Waya S. Phutdhawong
Keyword(s):  
Anticancer Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Human Cancer ◽  
Docking Study ◽  
Inhibitory Effect ◽  
Molecular Docking Study ◽  
Human Cancer Cell Lines ◽  
Activity Evaluation ◽  
Cancer Line

Azepinobisindole derivatives, the isomeric Iheyamine skeleton, was prepared and its anticancer activity evaluation were investigated against two human cancer cell lines, Hepatocellular carcinoma (HepG2) and human cervical cancer line (Hela) as well as the normal cell line (Vero cell line) using MTT assay. The anticancer activity results indicated that 2-methoxy-5-methyl-5H-azepino[2,3-b:4,5-bʹ]diindole was the most active derivative against tested cell lines. Additionally, molecular docking study in silico the possible inhibitory effect of cyclin-dependent kinase 2 (CDK2) by the azepinoindole revealed that all synthesized compounds fit well in the binding cavity of CDK2.

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