Synthesis and Biological Evaluation of New 1,3,4-Oxadiazoles as Potential Anticancer Agents and Enzyme Inhibitors

2018 ◽  
Vol 18 (6) ◽  
pp. 914-921 ◽  
Author(s):  
Leyla Yurttaş ◽  
Betül K. Çavuşoğlu ◽  
Gülşen A. Çiftçi ◽  
Halide E. Temel
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Enzyme Inhibitors ◽  
A549 Cells ◽  
Fibroblast Cell ◽  
Biological Evaluation ◽  
Rat Glioma ◽  
Human Lung Carcinoma ◽  
Nih 3T3

Background: 1,3,4-Oxadiazoles have been known with a wide variety of pharmacological activities including anticancer activity. Objective: In this study, novel 2,5-disubstituted 1,3,4-oxadiazole derivatives were synthesized and evaluated for determining their anticancer, anticholinesterase and lipoxygenase (LOX) inhibitory activity. Methods: All compounds were tested against C6 rat glioma, A549 human lung carcinoma and NIH/3T3 mouse embryo fibroblast cell lines to define cytotoxic concentrations and apoptosis induction levels which they cause. Results: Many of the compounds exhibited remarkable potency that compounds 2a, 2b, 2e, 2h and 2j against C6 cells and compounds 2a, 2b, 2d, 2g, 2i, 2j against A549 cells were found more active than cisplatin. Compound 2d namely, 2-[(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-chlorophenyl)ethan-1-one induced apoptosis of A549 cells with 74.9% whereas cisplatin caused 70.9% percentage. Conclusion: Among them, compounds 2d and 2j against A549 cell line, compounds 2b and 2e against both tumor cell lines showed selective cytotoxicity evaluating the inhibition concentration against NIH/3T3 cell line. None of the compounds showed significant acetylcholinesterase (AChE) and lipoxygenase inhibitory activities.

scholarly journals Design, Synthesis, Molecular Docking, ADME and Biological Evaluation Studies of Some New 1,3,4-oxadiazole Linked Benzimidazoles as Anticancer Agents and Aromatase Inhibitors

2021 ◽  
Author(s):  
ulviye acar çevik ◽  
Ismail Celik ◽  
Ayşen IŞIK ◽  
Yusuf Özkay ◽  
Zafer Asım Kaplancıklı
Keyword(s):  
Molecular Docking ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Evaluation Studies ◽  
Biological Evaluation ◽  
Binding Modes ◽  
Anticancer Activities ◽  
Mcf 7

Abstract In this study, due to the potential anticancer effects of the benzimidazole ring system, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC50 values of 5,165±0,211 μM and 5,995±0,264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 (mouse embryo fibroblast cell line) cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking against aromatase enzyme was performed to determine possible protein-ligand interactions and binding modes.

Design, Synthesis and Biological Evaluation of a Novel Series of Thiadiazole-Based Anticancer Agents as Potent Angiogenesis Inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Burcugül Altuğ-Tasa ◽  
Betül Kaya-Çavuşoğlu ◽  
Ayşe T. Koparal ◽  
Gülhan Turan ◽  
Ali S. Koparal ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Biological Evaluation ◽  
Tube Formation ◽  
In Vivo Studies ◽  
Human Cancer Cell Lines ◽  
Ic50 Values

Background: Thiadiazole has attracted a great deal of interest as a versatile heterocycle for the discovery and development of potent anticancer agents. Thiadiazole derivatives exert potent antitumor activity against a variety of human cancer cell lines through various mechanisms. Objective: The goal of this work was to design and synthesize thiadiazole-based anticancer agents with anti-angiogenic activity. Methods: N-aryl-2-[(5-(aryl)amino-1,3,4-thiadiazol-2-yl)thio]acetamides (4a-r) were synthesized via the reaction of 5-(aryl)amino-1,3,4- thiadiazole-2(3H)-thiones with N-(aryl)-2-chloroacetamides in the presence of potassium carbonate. The compounds were investigated for their cytotoxic effects on three cancer (A549, HepG2, SH-SY5Y), two normal (HUVEC and 3T3-L1) cell lines using MTT and WST1 assays. In order to examine whether the compounds have anti-angiogenic effects or not, HUVEC were cultured on matrigel matrix to create a vascular-like tube formation. Results: Compounds 4d, 4m and 4n were more effective on A549 human lung adenocarcinoma cells than cisplatin. The IC50 values of compounds 4d, 4m and 4n for A549 cell line were found to be 7.82±0.4, 12.5±0.22, 10.1±0.52 µM, respectively when compared with cisplatin (IC50= 20±0.51 µM), whilst their IC50 values for HUVEC cell line were determined as 138.7±0.84, 78±0.44, 177.6±0.2 µM, respectively after 48 h treatment. The concentrations (10-20-50 µM) of compounds 4d, 4e, 4l, 4m, 4n, 4q and 4r were found to inhibit vascular like tube formation. Conclusion: According to their anticancer and anti-angiogenic effects, compounds 4d, 4m and 4n may be potential anticancer agents for further in vivo studies.

Synthesis and Biological Evaluation of New Quinoline-Based Thiazolyl Hydrazone Derivatives as Potent Antifungal and Anticancer Agents

2018 ◽  
Vol 15 (2) ◽  
pp. 193-202 ◽  
Author(s):  
Ali Erguc ◽  
Mehlika Dilek Altintop ◽  
Ozlem Atli ◽  
Belgin Sever ◽  
Gokalp Iscan ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Mtt Assay ◽  
Anticancer Agents ◽  
Mouse Embryonic Fibroblast ◽  
Biological Evaluation ◽  
Diffusion Method ◽  
Breast Adenocarcinoma ◽  
Nih 3T3 ◽  
Mcf 7

Background: In medicinal chemistry, thiazoles have gained great importance in antifungal and anticancer drug design and development. Objectives: The aim of this study was to synthesize new quinoline-based thiazolyl hydrazone derivatives and evaluate their anticandidal and anticancer effects. Methods: New thiazolyl hydrazone derivatives were evaluated for their anticandidal effects using disc diffusion method. Ames MPF assay was carried out to determine the genotoxicity of the most effective antifungal derivative. MTT assay was also performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, MCF- 7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines. Methods: Results: 4-(4-Fluorophenyl)-2-(2-((quinolin-4-yl)methylene)hydrazinyl)thiazole (4) showed antifungal activity against Candida albicans and Candida krusei in the concentration of 1 mg/mL. In MTT and Ames MPF tests, it was determined that compound 4 did not show cytotoxic and genotoxic effects. MTT assay indicated that 4-(naphthalen-2-yl)-2-(2-((quinolin-4-yl)methylene) hydrazinyl)thiazole (10) showed more selective anticancer activity than cisplatin against A549 and MCF-7 cell lines. Besides, 4-(4-chlorophenyl)-2-(2-((quinolin-4-yl)methylene)hydrazinyl)thiazole (5) exhibited more selective anticancer activity than cisplatin against HepG2 cell line. Conclusion: Due to their high selectivity index, these compounds are considered as candidate compounds to participate in further research.

Design, Synthesis and Biological Evaluation of a Novel Series of Indole-3- Carboxamide Derivatives for Cancer Treatment as EGFR Inhibitors

2018 ◽  
Vol 15 (1) ◽  
pp. 70-83 ◽  
Author(s):  
Lan Zhang ◽  
Xin-Shan Deng ◽  
Guang-Peng Meng ◽  
Chao Zhang ◽  
Cong-Chong Liu ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Egfr Inhibitors ◽  
Target Compound ◽  
Anticancer Activities ◽  
Aberrant Expression

Background: As reported EGFR is a sialoglycoprotein with tyrosine kinase activity involved in control of cellular survival, multiplication, differentiation and metastasis. Dysregulation or aberrant expression of EGFR has been implicated in cell transformation and having oncogenic roles in a number of human cancers. Therefore EGFR has become a significant target for developing targeted therapy for cancer. Methods: A novel series of indole-3-carboxamide derivatives as EGFR inhibitors were designed, synthesized and evaluated for the anticancer activity in vitro against three EGFR high-expressed cancer cell lines (A549, HeLa, and SW480), one EGFR low-expressed cell line (HepG2) and one human liver normal cell line (HL7702) by MTT assay. Results: The target compounds 6c, 6f, 6i, 6j, 6l, 6r, 6u and 6x exhibited potent anticancer activities against the three tested cancer cell lines and weak cytotoxic effects on HepG2, which imply that the target compounds are probably effective in inhibiting EGFR. And they also did not show measurable activities in HL7702, which imply the target compounds are likely to overcome the nonspecific toxicity against normal cells. Particularly, the target compound 6x indicated equal to the positive control erlotinib. In addition, molecular docking studies demonstrated the target compound 6x may be the potential inhibitor to EGFR. Conclusion: A new EGFR inhibitor scaffold and a preliminary discussion on their SARs provide promising opportunities to guide further research on indole-3-carboxamide derivatives as novel anticancer agents.

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 Synthesis, Molecular Modeling and Biological Evaluation of Novel Imatinib Derivatives as Anticancer Agents

2021 ◽  
Author(s):  
Fulya Günay ◽  
Sevcan Balta ◽  
Yuk Yin Ng ◽  
Özlem Ulucan ◽  
Zuhal Turgut ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Kinase Inhibitor ◽  
Coupling Reaction ◽  
Leukemic Cell ◽  
Kinase Domain ◽  
Biological Evaluation ◽  
Docking Simulations ◽  
Abl Kinase

Abstract Different derivatives of imatinib, the first targeted BCR-ABL fusion tyrosine kinase inhibitor, were synthesized by a 3-step reaction method. Firstly, benzamide derivative was obtained then aryl piperazine groups or morpholine were linked by the SN2 reaction. Lastly, palladium catalyzed C-N coupling reaction was conducted with hetaryl amine groups. The structures of the new compounds were characterized by spectroscopic methods. For quantitative evaluation of the biological activity of the compounds, MTT assays were performed, where four BCR-ABL negative leukemic cell lines (Jurkat, REH, NALM6 and MOLT4), one BCR-ABL+ cell line (K562) and one non-leukemic cell line (Hek293T) were incubated with various concentrations of the derivatives. Although imatinib was specifically designed for the BCR-ABL protein, our results showed that it was also effective on BCR-ABL negative cell lines except for REH cell line. Molecular docking simulations suggest that except for compound 6, the compounds prefer a DFG-out conformation of the ABL kinase domain. Among them, compound 10 has the highest affinity for ABL kinase domain that is close to the affinity of imatinib. The common rings between compound 10 and imatinib adopt exactly the same conformation and same type of interactions in the ATP binding site with the ABL kinase domain.

Design, Synthesis, In vitro and In silico Evaluation of New Hydrazonebased Antitumor Agents as Potent Akt Inhibitors

2020 ◽  
Vol 17 (11) ◽  
pp. 1380-1392
Author(s):  
Emine Merve Güngör ◽  
Mehlika Dilek Altıntop ◽  
Belgin Sever ◽  
Gülşen Akalın Çiftçi
Keyword(s):  
Cell Line ◽  
Anticancer Agents ◽  
In Silico ◽  
Antitumor Agents ◽  
Colorimetric Assay ◽  
Fibroblast Cell ◽  
Lipinski’S Rule ◽  
In Silico Docking ◽  
Embryonic Fibroblast

Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt. Objectives: The objective of this work was to identify potent anticancer agents targeting Akt. Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

Synthesis and Anticancer Activity of New Hydrazide-hydrazones and Their Pd(II) Complexes

2019 ◽  
Vol 16 (5) ◽  
pp. 522-532 ◽  
Author(s):  
Bedia Kocyigit-Kaymakcioglu ◽  
Senem Sinem Yazici ◽  
Fatih Tok ◽  
Miriş Dikmen ◽  
Selin Engür ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Anticancer Activity ◽  
Cell Line ◽  
Cancer Cell ◽  
Cytotoxic Effect ◽  
A549 Cells ◽  
Cancer Cell Line ◽  
Fibroblast Cell ◽  
Reference Drug ◽  
A549 Cancer Cell Line

Background: Hydrazones, one of the important classes of organic molecules, are pharmaceutical agents comprising –CO-NH-N=CH- group in the structure therefore and exhibiting significant biological activity. Methods: 5-Chloro-N’-[(substituted)methylidene] pyrazine-2-carbohydrazide (3a-g) and their Pd(II) complexes (4a-h) were synthesized and investigated in vitro anticancer activity on A549, Caco2 cancer and normal 3T3 fibroblast cell lines, using the MTT assay. Results: Anticancer activity screening results revealed that some compounds showed remarkable cytotoxic effect. Among them, 5-chloro-N'-[(4-hydroxyphenyl)methylidene] pyrazine-2-carbohydrazide (3c) displayed higher cytotoxic activity against A549 cancer cell line than the reference drug cisplatin. Conclusion: Compound 3c showed high cytotoxic activity against A549 cancer cell line but it showed low cytotoxic effect against normal 3T3 fibroblast cell line. Antiproliferative and antimetastatic effects of 3c were determined by the real-time monitoring of cell proliferative system (RTCA DP). The cell proliferation, metastatic and invasive activities of A549 cells were decreased due to increased concentration of 3c.

Synthesis and Biological Evaluation of Novel 4,5,6,7-Tetrahydrobenzo[D]-Thiazol-2- Yl Derivatives Derived from Dimedone with Anti-Tumor, C-Met, Tyrosine Kinase and Pim-1 Inhibitions

2019 ◽  
Vol 19 (12) ◽  
pp. 1438-1453 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Amr S. Abouzied ◽  
Nermeen S. Abbas
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Cell ◽  
Cell Lines ◽  
Single Molecule ◽  
Anticancer Agents ◽  
Biological Evaluation ◽  
New Drugs ◽  
Tumor Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range

Background: Dimedone and thiazole moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. Thiazole derivatives are a very important class of compounds due to their wide range of pharmaceutical and therapeutic activities. On the other hand, dimedone is used to synthesize many therapeutically active compounds. Therefore, the combination of both moieties through a single molecule to produce heterocyclic compounds will produce excellent anticancer agents. Objective: The present work reports the synthesis of 47 new substances belonging to two classes of compounds: Dimedone and thiazoles, with the purpose of developing new drugs that present high specificity for tumor cells and low toxicity to the organism. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7-tetrahydrobenzo[d]-thiazol-2-yl derivatives using the reaction of the 2-bromodimedone with cyanothioacetamide. Methods: The reaction of 2-bromodimedone with cyanothioacetamide gave the 4,5,6,7-tetrahydrobenzo[d]- thiazol-2-yl derivative 4. The reactivity of compound 4 towards some chemical reagents was observed to produce different heterocyclic derivatives. Results: A cytotoxic screening was performed to evaluate the performance of the new derivatives in six tumor cell lines. Thirteen compounds were shown to be promising toward the tumor cell lines which were further evaluated toward five tyrosine kinases. Conclusion: The results of antitumor screening showed that many of the tested compounds were of high inhibition towards the tested cell lines. Compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 21b, 21c, 20d and 21d were the most potent compounds toward c-Met kinase and PC-3 cell line. The most promising compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 20c, 20d, 21b, 21c and 21d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6c, 11b, 11d, 14b, 15c, and 20d were selected to examine their Pim-1 kinase inhibition activity the results revealed that compounds 11b, 11d and 15c had high activities.

Novel Anthraquinone Derivatives as Dual Inhibitors of Topoisomerase 2 and Casein Kinase 2: In Silico Studies, Synthesis and Biological Evaluation on Leukemic Cell Lines

2019 ◽  
Vol 18 (11) ◽  
pp. 1551-1562 ◽  
Author(s):  
Abbas Kabir ◽  
Kalpana Tilekar ◽  
Neha Upadhyay ◽  
C.S. Ramaa
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Biological Evaluation ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Cell Cycle Analysis ◽  
Protein Targets ◽  
Topoisomerase 2 ◽  
Dual Inhibitors

Background: Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for “multiple targeting”, wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2. Objective: With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects. Methods: Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis. Results: The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase. Conclusion: We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.

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