Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7

Abdelhaleem, Eman F.; Abdelhameid, Mohammed K.; Kassab, Asmaa E.; Kandeel, M. M.

doi:10.1016/j.ejmech.2017.10.075

Cited by 67 publications

(25 citation statements)

References 19 publications

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“…Several molecular descriptors were calculated for each compound employing a calculated molecular properties module. The 3 D structures of the training set compounds were imported into the Discovery Studio program to calculate various molecular descriptors including energies of highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) for each of the synthesized compound 39 . First, Genetic function approximation (GFA) which is a useful statistical analysis tool to correlate biological activity or property with chemical characteristics of molecules was employed to search for the best possible QSAR regression equation, then Multiple linear regression (MLR) analysis were employed to optimize QSAR model 39 .The MLRTemp Model equation bearing the relevant descriptors shows our best performing QSAR models is given as the following equation: …”

Section: Resultsmentioning

confidence: 99%

“…HepG-2 cells were treated with compounds 5 and 21 at their IC 50 values for 24 h. After treatment, cells were washed twice with ice-cold phosphate buffer saline (PBS), collected by centrifugation, and fixed in ice-cold 70% (v/v) ethanol, washed with PBS, re-suspended with 0.1 mg/mL RNase, stained with 40 mg/mL propidium iodide (PI), and analyzed by flow cytometry using FACS Calibur (Becton Dickinson) 39 . The cell cycle distributions were calculated using Cell-Quest software (Becton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

“…Combined with our previous studies on HCC and dual cytotoxic agents 38 . , 39 ., we attempted to combine anti-angiogenic and tubulin inhibition activities into several derivatives by using a common pharmacophoric moiety ( ortho - N -arylamino- N,N -diaryl carboxamide) as a template to act as a dual angiokinase and tubulin polymerization inhibitor. To increase the binding of the novel molecules to both biological targets, the structure of the template is enriched with additional kinase and colchicine site interacting moieties.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors

Abdelhameid

Labib

Negmeldin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this work, design, synthesis, and screening of thiophene carboxamides 4–13 and 16–23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors

Abdelhameid

Labib

Negmeldin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…A small number of ‘local’ QSAR models have been published (44–47), focused on the cytotoxicity of a limited number of similar substances against one or several cancer cell lines, but such models have a narrow range of chemical structures and a narrow domain of applicability (48). Our study is one of the few where cytotoxicity assessed on a cancer cell line (SK-MEL-5) is explored through ‘global’ QSAR modelling.…”

Section: Discussionmentioning

confidence: 99%

Development of QSAR machine learning-based models to forecast the effect of substances on malignant melanoma cells

et al. 2019

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SK-MEL-5 is a human melanoma cell line that has been used in various studies to explore new therapies against melanoma in different in vitro experiments. Based on this study we report on the development of quantitative structure-activity relationship (QSAR) models able to predict the cytotoxic effect of diverse chemical compounds on this cancer cell line. The dataset of cytotoxic and inactive compounds were downloaded from the PubChem database. It contains the data for all chemical compounds for which cytotoxicity results expressed by GI 50 was recorded. In total 13 blocks of molecular descriptors were computed and used, after appropriate pre-processing in building QSAR models with four machine learning classifiers: Random forest (RF), gradient boosting, support vector machine and random k-nearest neighbors. Among the 186 models reported none had a positive predictive value (PPV) higher than 0.90 in both nested cross-validation and on an external dataset testing, but 7 models had a PPV higher than 0.85 in both evaluations, all seven using the RFs algorithm as a classifier, and topological descriptors, information indices, 2D-autocorrelation descriptors, P-VSA-like descriptors, and edge-adjacency descriptors as sets of features used for classification. The y-scrambling test was associated with considerably worse performance (confirming the non-random character of the models) and the applicability domain was assessed through three different methods.

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“…Thus, a remarkable amount of studies focus on alkyl/aryl substituted urea moieties for the rational design of new drug candidates . Various urea‐containing molecules have been reported with diverse biological applications as antibacterial, antitubercular, antifungal, anti‐inflammatory, antiviral, antidepressant, and anticancer agents . Among them, various aryl/alkyl‐substituted urea derivatives were reported with their antimicrobial activities .…”

Section: Introductionmentioning

confidence: 93%

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

Doğan

Buran

Gündüz

et al. 2019

Chemistry & Biodiversity

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The discovery of new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a-10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1'-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis β-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds. Scheme 1. Synthetic scheme for the preparation of the key compound, 2,2'-[disulfanediylbis(methylene)]dibenzoic acid (5).

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Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7

Cited by 67 publications

References 19 publications

Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors

Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors

Development of QSAR machine learning-based models to forecast the effect of substances on malignant melanoma cells

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

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