Synthesis, Biological Evaluation and Docking Study of New Pyrimidine Compounds as Anticancer Agents

Drug Research ◽  
2020 ◽  
Author(s):  
Shahin Boumi ◽  
Jafar Moghimirad ◽  
Seyed Nasser Ostad ◽  
Massoud Amanlou ◽  
Shohreh Tavajohi ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Binding Site ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Docking Study ◽  
Biological Evaluation ◽  
Cytotoxic Activities ◽  
Aryl Group ◽  
The Third ◽  
Colchicine Binding Site

Abstract Objectives The microtubule is composed of αβ tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit Colchicine binding site. Methods In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic activities were evaluated and molecular docking studies were performed. Twelve compounds of pyrimidine were synthesized in 3 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by sulfoxide-methylene moiety and in the third group sulfone-methylene group was used as spacer. Results The cytotoxic activity of these compounds were evaluated against 3 different cancerous cell lines (HT-29, MCF-7, T47D) as well as normal cell line (NIH3T3). Compounds in group 2 showed the best cytotoxicity and compound 7d showed the most potent cytotoxic activity against all cell lines. Molecular modelling studies revealed that compound 7d could strongly bind to the colchicine binding site of tubulin. Conclusion Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents.

Synthesis, evaluation of biological activity, docking and molecular dynamic studies of pyrimidine derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Shahin Boumi ◽  
Jafar Moghimirad ◽  
Massod Amanlou ◽  
Seyed Nasser Ostad ◽  
Shohreh Tavajohi ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Binding Site ◽  
Cell Line ◽  
Cell Lines ◽  
Docking Studies ◽  
Cytotoxic Activities ◽  
Tubulin Polymerization ◽  
Pyrimidine Derivatives ◽  
Aryl Group ◽  
Colchicine Binding Site

Background: The microtubule is composed of αβ-tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit colchicine binding site. Objective: In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic activities were evaluated and molecular docking studies were performed. Methods: Twenty compounds of pyrimidine were synthesized in 2 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by S-CH2- triazole moiety. The cytotoxic activity of these compounds was evaluated against 4 different cell lines (HT-29, MCF-7, T47D, NIH3T3). Results: Compounds 6d, 6m, 6p showed potent cytotoxic activity against MCF7 cancerous cell lines. Between these compounds, compound 6p did not show cytotoxic activity against NIH- 3T3 (normal cell) cell line. Docking studies show that these compounds occupy colchicine binding site in tubulin protein and probably their anticancer mechanism is inhibition of tubulin polymerization. Conclusion : Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents. Attention to the selectivity index of 6p on MCF7 cell line could be valuable in design new chemical agents for treatment of breast cancer.

Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

2019 ◽  
Vol 16 (11) ◽  
pp. 1194-1201 ◽  
Author(s):  
Farhad Saravani ◽  
Ebrahim Saeedian Moghadam ◽  
Hafezeh Salehabadi ◽  
Seyednasser Ostad ◽  
Morteza Pirali Hamedani ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Cytotoxic Activity ◽  
Binding Site ◽  
Cell Line ◽  
Cell Lines ◽  
Tubulin Polymerization ◽  
Adenocarcinoma Cell Line ◽  
Adenocarcinoma Cell ◽  
Colchicine Binding Site ◽  
Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

scholarly journals Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1613 ◽  
Author(s):  
Angelika A. Adamus-Grabicka ◽  
Magdalena Markowicz-Piasecka ◽  
Marcin Cieślak ◽  
Karolina Królewska-Golińska ◽  
Paweł Hikisz ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Dna Cleavage ◽  
Cancer Cell Lines ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Proliferative Potential ◽  
Monoclinic System

A series of 3-benzylidenechrmanones 1, 3, 5, 7, 9 and their spiropyrazoline analogues 2, 4, 6, 8, 10 were synthesized. X-ray analysis confirms that compounds 2 and 8 crystallize in a monoclinic system in P21/n space groups with one and three molecules in each asymmetric unit. The crystal lattice of the analyzed compounds is enhanced by hydrogen bonds. The primary aim of the study was to evaluate the anti-proliferative potential of 3-benzylidenechromanones and their spiropyrazoline analogues towards four cancer cell lines. Our results indicate that parent compounds 1 and 9 with a phenyl ring at C2 have lower cytotoxic activity against cancer cell lines than their spiropyrazolines analogues. Analysis of IC50 values showed that the compounds 3 and 7 exhibited higher cytotoxic activity against cancer cells, being more active than the reference compound (4-chromanone or quercetin). The results of this study indicate that the incorporation of a pyrazoline ring into the 3-arylideneflavanone results in an improvement of the compounds’ activity and therefore it may be of use in the search of new anticancer agents. Further analysis allowed us to demonstrate the compounds to have a strong inhibitory effect on the cell cycle. For instance, compounds 2, 10 induced 60% of HL-60 cells to be arrested in G2/M phase. Using a DNA-cleavage protection assay we also demonstrated that tested compounds interact with DNA. All compounds at the concentrations corresponding to cytotoxic properties are not toxic towards red blood cells, and do not contribute to hemolysis of RBCs.

scholarly journals Design, Synthesis and Biological Evaluation of Novel Piperazinone Derivatives as Cytotoxic Agents

2020 ◽  
Vol 10 (3) ◽  
pp. 423-429
Author(s):  
Saeed Ghasemi ◽  
Simin Sharifi ◽  
Javid Shahbazi Mojarrad
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Normal Cell ◽  
Colorimetric Assay ◽  
Fetal Lung ◽  
Biological Evaluation ◽  
Cytotoxic Agents ◽  
Lung Fibroblasts ◽  
Assay Method ◽  
Cytotoxic Activities

Purpose : In this study, a series of piperazin-2-one derivatives were prepared through bioisosteric substitution of the imidazole ring of L-778,123 (imidazole-containing FTase inhibitor) and rearrangement of groups based on the tipifarnib structure. Final compounds were evaluated for their cytotoxic activities on cancer and normal cell lines by MTT assay. Methods: Methyl α-bromophenylacetic acid and 1-(3-chlorophenyl) piperazin-2-one were synthesized using previously described methods. Methyl 2-(4-chlorophenyl)-2-(4-(3- chlorophenyl)-3-oxopiperazin-1-yl) acetate was prepared by reaction between these two compounds in presence of potassium carbonate. Finally, methoxy group of ester was substituted by various amines such as guanidine, thiourea, urea and hydrazide. The synthesized compounds were tested for their cytotoxicity against colon cancer (HT-29) and lung cancer (A549) cell lines as well as MRC-5 (normal fetal lung fibroblasts) cells as a healthy cell line using MTT colorimetric assay method. Results: Replacement of imidazole moiety with guanidine, thiourea, and hydrazide could increase cytotoxicity toward all three cell lines. Some substituents, such as amine, urea, and hydroxylamine exhibited significant cytotoxicity (<500 µM) but lower than L-778,123 as standard compound. Hydroxyl and methoxy substituents did not show significant cytotoxicity. Imidazole substituent group revealed cytotoxicity similar to L-778,123 All compounds showed lower cytotoxic activity against normal cell lines compared with cancer cell lines. Conclusion: It seems the electron density of substituted groups and rearrangement of groups may significantly increase cytotoxic activity

Design, Synthesis and Biological Evaluation of Novel Diaryl Pyrazole Derivatives as Anticancer Agents

2020 ◽  
Vol 17 (3) ◽  
pp. 216-223
Author(s):  
Jalal Nourmahammadi ◽  
Ebrahim Saeedian Moghadam ◽  
Zahra Shahsavari ◽  
Mohsen Amini
Keyword(s):  
Cytotoxic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Annexin V ◽  
Biological Evaluation ◽  
Pyrazole Derivatives ◽  
Cell Viability Assay ◽  
Viability Assay ◽  
Cancerous Cell

Cancer is one of the major causes of mortality all around the world. Globally, nearly 1 in 6 deaths is due to cancer. Researchers are trying to synthesize new anticancer agents. Previous studies demonstrated that some pyrazole derivatives could be considered as potential anticancer agents. Herein, ten novel derivatives of 1,5-diarylpyrazole were synthesized in four step reactions and cytotoxic activity was investigated by MTT cell viability assay. All of the compounds were characterized by 1H NMR and 13C NMR and their purity was confirmed by elemental analysis. The cytotoxicity was determined against three cancerous cell lines (HT-29, U87MG and MDA-MB 468) and AGO1522 as a normal cell line. Compound 5a showed the best cytotoxic activity on cancerous cell lines in comparison to paclitaxel. Annexin V/ PI staining assay also showed that compounds 5a and 5i would lead to significant apoptosis induction in MDA-MB 486 cell line.

scholarly journals Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3466
Author(s):  
Shoujie Li ◽  
Mingjie Gao ◽  
Xin Nian ◽  
Liyu Zhang ◽  
Jinjie Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Biological Activities ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Nucleus Structure

Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.

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