Four-Component Synthesis of 1,2-Dihydropyridine Derivatives and their Evaluation as Anticancer Agents (original) (raw)
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Synthesis and Evaluation of New Series of 1,4-Dihydropyridine Derivatives as Anticancer Agents
International Journal of Sciences: Basic and Applied Research, 2016
1,4-dihydropyridine derivatives represent one of the important classes of compounds possessing a wide variety of biological activities including anticancer activity. In the present study, (4-Alkyl/Aryl-1-substituted 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxilicacid, 3,5-bis [2(aminothioxomethyl)hydrazides]) (6 a-l) were synthesized by the reaction of 4-alkyl/aryl-3,5-dicarboalkoxy-2,6-dimethyl-1,4-dihydropyridines (4 a-l) with thisemicarbazide and evaluated for their anti-cancer properties. All the synthesized compounds were characterized by IR, NMR and Mass spectra and were screened to evaluating for anticancer activity against three cell lines (MCF-7, HeLa and Hep G 2 ) by using MTT assay method. The results showed that compounds 6j and 6l showed significant cytotoxicity with IC 50 values ranging from 56µM - 74µM.
2018
CDK2, which plays a vital role as a regulator of cell growth, is one of the intensely studied TK targets of anticancer inhibitors. The present investigation dealt with design (docking and binding energy), which used to select the promising proposed compounds for the synthesis of novel, diverse 14 pyrido[2,3-d]pyrimidine derivatives as potential anticancer agents targeting CDK2. All the newly synthesized compounds were screened for their anticancer activity against MCF-7 and CaCO2 and 14 compounds were found to be active. Compounds 6c and 8d showed significant activity with IC50 values 7.4 and 5.5 on MCF-7 respectively. Most of the synthesized compounds were subjected to enzyme assay (CDK2 TK) for measuring their inhibitory activity. The preliminary results revealed that compound 8d, which proves potent inhibitory activity toward tumor growth and potent activity on the CDK2 TK enzyme with 89% inhibition compared to ATP would be a potential anticancer agent.
Synthesis and anticancer activity of new dihydropyrimidinone derivatives
European journal of medicinal chemistry, 2018
A series of dihydropyrimidinone derivatives bearing various N-heterocyclic moieties was designed and synthesized. Twelve new compounds were screened for their cytotoxic activity using 60 cancer cell lines according to NCI (USA) protocol. Compound 19 showed a significant activity against NCI-H460, SK-MEL-5, and HL-60 (TB) cell lines with growth inhibition 88%, 86% and 85%, respectively, and was found to be more safe on normal cells when compared to doxorubicin. Enzyme inhibition assay was performed for compound 19 against mTOR (IC = 0.64 μM) and VEGFR-2 (IC = 1.97 μM) to show high potency in comparison to rapamycin (IC = 0.43 μM) and sorafenib (IC = 0.3 μM) as references, respectively. Cell cycle analysis of A549 cells treated with 19 showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
Madridge J Pharm Res, 2019
Background and Objective: Inflammation is believed to incite carcinogenesis by causing cell and genome damage. Tetrahydropyridines have gained significant synthetic interest because they constitute biologically active features of pharmaceutical agents. Previous tetrahydropyridines developed by our research group were effective in inhibiting inflammation. Since there is a relationship between inflammation and cancer, the objective of this manuscript is to expand our prior study to determine the anti-cancer activity of novel tetrahydropyridine analogs. Materials and methods: 3-Ethylpyridine reacted with O-mesitylenesulfonylhydroxylamine to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines. The evaluation of these analogs cytotoxicity against Ishikawa, MCF-7, and MDA-MB-231 cell lines were determined after 72 hours of drug exposure employing CellTiter-Glo assay. To explore the interaction between the tetrahydropyridine derivatives and estrogen receptor alpha, SYBYL-X 2.1 was used to determine the best bioactive conformations of the tetrahydropyridine derivatives for the active site of the receptor. Results: Four novel N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The four tetrahydropyridine analogs exhibited some anti-cancer activity. Based on the molecular modeling studies, EH3 was expected to have the best antiproliferative activity due to having the highest docking score for ERα. However, EH2 had the best antiproliferative activity. Nevertheless, the biological screening and molecular modeling can provide insight to help with the design of more biologically active compounds as potential anti-cancer agents.
Two series of novel substituted 1,4-dihydropyridine derivatives incorporating nitrogen mustard pharmacophore hybrids without spacer DHP-M (4a–4d) and with ethyl spacer DHP-L-M (8a–8g) were designed and synthesized. They were subjected to in silico ADME prediction study to check their drug-like properties and evaluated for their cytotoxicity against: A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) human cancer cell lines in vitro using 3-(4,5- dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against chlorambucil and docetaxel. Majority of the test compounds exhibited moderate to significant cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by DHP-M (4a). This may be due to the less steric hindrance offered by 4a.
Journal of Oncology
The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analy...
Synthesis and Evaluation of Triazolyl Dihydropyrimidines as Potential Anticancer Agents
International Journal of Chemistry, 2018
Novel N – triazolyl 3(a-f) and O-triazolyl (4a-f) derivatives of 4, 6-diaryl-1, 4-dihydropyrimidines were synthesized through mannich reaction. All compounds were characterized by physical and spectral data. These compounds were screened for in vitro efficiency in human breast cancer cell (MCF-7&MDA-MB-231) lines and found to have very good anti-proliferative activity. Among all compounds of 4b, 3e, 4e endowed with lesser respective IC50 values of 31.94, 55.73, 55.03 µM in MCF-7 cells and 41.50, 35.28, 32.06 µM in MDA-MB 231 cells by MTT assay. In further studies, Compounds 4b, 3e, 4e were found to arrest cell growth at S phase in MCF-7 cells. In MDA-MB 231 cells, 4b, 4e were found to arrest the cells in S phase, and compound 3e found to arrest G2/M phase when compared to the standard drug tamoxifen, arrested S phase in MCF-7 cells and G0/G1 phase in MDA-MB 231 cells.
Archiv der Pharmazie, 2010
A series of twenty new 4‐substituted‐2,6‐dimethyl‐3,5‐bis‐N‐(heteroaryl)‐carbamoyl‐1,4‐dihydropyridines have been prepared from a three‐component one‐pot condensation reaction of N‐heteroaryl acetoacetamide, an aromatic/heteroaromatic aldehyde, and ammonium acetate under four different experimental conditions. Except for the conventional method, all the experimental conditions were simple, eco‐friendly, economical, and the reactions were rapid and high‐yielding. The methods employed have been compared in terms of yields, cost, and simplicity. The synthesized compounds were characterized by different spectroscopic techniques and evaluated for their in‐vitro anticancer, antibacterial, and antitubercular activities. Amongst the compounds tested, compound 25 exhibited the highest anticancer activity while compounds 14 and 18 exhibited significant antibacterial and antitubercular activities.
Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones
International Journal of Molecular Sciences
Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine analogue (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic i...
RSC Advances, 2016
The search for novel anticancer agents with higher selectivity and lower toxicity remains a priority. This work aimed to design more potent and selective anticancer molecules among the class of 3,4-dihydropyrimidin-2-(1H)-ones. Thus, a series of molecules was synthesized through the Biginelli reaction and their in vitro antiproliferative activity was evaluated in different human cell lines. Then, a quantitative structure-activity relationship (QSAR) analysis was performed using Bayesian regularized artificial neural networks to model the relationships between in silico molecular descriptors and the observed antiproliferative activity of molecules across the tested cell lines. Interestingly, among the compounds prepared, the molecules containing chloro atoms in their structure demonstrated a relevant potency and a selective antiproliferative activity against a novel hepatic cancer cell line (HepaRG) without exhibiting noticeable cytotoxicity in normal dermal cells (NHDF). However, in prostatic (LNCaP), colon (Caco-2) and breast (T47D and MCF-7) cancer cell lines generally the compounds did not exhibit relevant cytoxicity. A statistically valid QSAR model was obtained (internal validation Q(2) - 0.663, RMSECV - 0.071, 10-fold cross-validation procedure, and external validation R-pred(2) = 0.740, RMSE = 0.077), which allowed the analysis of the involved relationships between molecular descriptors and the reliable prediction of the antiproliferative activity for hypothetical related compounds in the studied cell lines. Moreover, flow cytometry analysis showed that in HepaRG and MCF-7 cell lines, compound 16 did not decrease cell viability but, interestingly, led to an accumulation of cells in the G(0)/G(1) phase of the cell cycle. Therefore, chlorinated 3,4-dihydropyrimidin-2-(1H)-ones may be considered promising compounds for further optimization as new antitumor agents.