scholarly journals Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5134
Author(s):  
Santiago García ◽  
Itzel Mercado-Sánchez ◽  
Luis Bahena ◽  
Yolanda Alcaraz ◽  
Marco A. García-Revilla ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Anticancer Agents ◽  
Hydroxamic Acid ◽  
Active Sites ◽  
Kinase Inhibitor ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Fluorescent Properties ◽  
Hydroxamic Acid Derivatives

Coumarin-hydroxamic acid derivatives 7a–k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30–87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.

Synthesis, biological evaluation and molecular docking studies of 1,3-benzoxazine derivatives as potential anticancer agents

2013 ◽  
Vol 22 (11) ◽  
pp. 5256-5266 ◽  
Author(s):  
Vikas Garg ◽  
Ankit Kumar ◽  
Anurag Chaudhary ◽  
Saurabh Agrawal ◽  
Praveen Tomar ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies

scholarly journals In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

2019 ◽  
Vol 21 (1) ◽  
pp. 219 ◽  
Author(s):  
Shana V. Stoddard ◽  
Kyra Dodson ◽  
Kamesha Adams ◽  
Davita L. Watkins
Keyword(s):  
In Silico ◽  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Docking Studies ◽  
Design Guidelines ◽  
Inhibitor Binding ◽  
Design And Optimization ◽  
Histone Deacetylase 4 ◽  
Prime Target ◽  
Hydroxamic Acid Derivatives

Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas.

scholarly journals Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents

2020 ◽  
Vol 97 ◽  
pp. 103664 ◽  
Author(s):  
Greta Klejborowska ◽  
Alicja Urbaniak ◽  
Ewa Maj ◽  
Jordane Preto ◽  
Mahshad Moshari ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies

scholarly journals Gene Expression Profiling Reveals Progesterone-Mediated Cell Cycle and Immunoregulatory Roles of Hoxa-10 in the Preimplantation Uterus

2003 ◽  
Vol 17 (4) ◽  
pp. 610-627 ◽  
Author(s):  
Mylene W. M. Yao ◽  
Hyunjung Lim ◽  
Daniel J. Schust ◽  
Sung E. Choe ◽  
Anna Farago ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Pregnancy Loss ◽  
Stromal Cell ◽  
Recurrent Pregnancy Loss ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Local Immunosuppression

Abstract Human infertility and recurrent pregnancy loss caused by implantation defects are poorly understood. Hoxa-10-deficient female mice have severe infertility and recurrent pregnancy loss due to defective uterine implantation. Gene expression profiling experiments reveal that Hoxa-10 is an important regulator of two critical events in implantation: stromal cell proliferation and local immunosuppression. At the time of implantation, Hoxa-10 mediates the progesterone-stimulated proliferation of uterine stromal cells. Hoxa-10 mutants express a stromal cell proliferation defect that is accompanied by quantitative or spatial alterations in the expression of two cyclin-dependent kinase inhibitor genes, p57 and p15. Hoxa-10 deficiencyFS also leads to a severe local immunological disturbance, characterized by a polyclonal proliferation of T cells, that occurs in place of the normal progesterone-mediated immunosuppression in the periimplantation uterus.

Synthesis, biological evaluation and molecular docking studies of novel 1-(4,5-dihydro-1H-pyrazol-1-yl)ethanone-containing 1-methylindol derivatives as potential tubulin assembling inhibitors

RSC Advances ◽  
2016 ◽  
Vol 6 (36) ◽  
pp. 30412-30424 ◽  
Author(s):  
Meng-Ru Yang ◽  
Ya-Juan Qin ◽  
Chen Chen ◽  
Ya-Liang Zhang ◽  
Bo-Yan Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies

A series of novel compounds (6a–6v) containing 1-methylindol and 1-(4,5-dihydro-1H-pyrazol-1-yl)ethanone skeleton were designed, synthesized and evaluated as potential anticancer agents.

Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

2020 ◽  
Vol 19 (17) ◽  
pp. 2120-2129 ◽  
Author(s):  
Sakineh Dadashpour ◽  
Tuba T. Küçükkılınç ◽  
Ayse Ercan ◽  
Seyed J. Hosseinimehr ◽  
Nima Naderi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Biological Evaluation ◽  
Kinase Assay ◽  
Drug Candidate ◽  
Surface Receptors ◽  
Anticancer Mechanism

Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

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