Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors

2018 ◽  
Vol 18 (6) ◽  
pp. 891-902 ◽  
Author(s):  
Srinu Bodige ◽  
Parameshwar Ravula ◽  
Kali Charan Gulipalli ◽  
Srinivas Endoori ◽  
J.N. Narendra Sharath Chandra ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Intracellular Signaling ◽  
Research Work ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Intracellular Enzyme ◽  
Ht 29 ◽  
Mcf 7

Background: Phosphatidylinositol-3-kinase α (PI3Kα) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. Methods: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3Kα enzyme. Results: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 µM and 4.25 µM, respectively. Further, the same compound also exhibited potent PI3Kα inhibitory activity with IC50 value of 1.26 µM. Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.

scholarly journals Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 123
Author(s):  
Elshaymaa I. Elmongy ◽  
Nashwah G. M. Attallah ◽  
Najla Altwaijry ◽  
Manal Mubarak AlKahtani ◽  
Hanan Ali Henidi
Keyword(s):  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Apoptotic Cell ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Significant Inhibition ◽  
Design And Synthesis ◽  
Kinase Inhibitory Activity ◽  
Ht 29 ◽  
Mcf 7

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

scholarly journals A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 412
Author(s):  
Mohammad M. Al-Sanea ◽  
Ahmad J. Obaidullah ◽  
Mohamed E. Shaker ◽  
Garri Chilingaryan ◽  
Mohammed M. Alanazi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Line ◽  
Inhibitory Activity ◽  
Flow Cytometric Analysis ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Intrinsic Activity ◽  
Binding Interaction ◽  
Mcf 7

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold (HI 5) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound. Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies. Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers (syn and anti) is responsible for binding affinity and intrinsic activity of HI 5. However, the molecular dynamic studies have confirmed that the syn-isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity. Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.

Anticancer Activity of Some Bisbenzimidazoles

2011 ◽  
Vol 66 (9-10) ◽  
pp. 465-470 ◽  
Author(s):  
İlhan Işıkdağ ◽  
Yusuf Özkay ◽  
Zerrin İncesu ◽  
Gülşen Akalın
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Topoisomerase I ◽  
Carcinoma Cell ◽  
Dna Topoisomerase ◽  
Carcinoma Cell Lines ◽  
Activity Screening ◽  
Breast Carcinoma Cell Lines ◽  
Ht 29 ◽  
Mcf 7

The discovery of DNA topoisomerases has added a new dimension to the study of anticancer drugs. Bisbenzimidazole derivatives are important compounds known as DNA topoisomerase I inhibitors. In the present study, some symmetrical bisbenzimidazole derivatives were synthesized and investigated for their anticancer activity. Anticancer activity screening was applied on HT-29 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines by investigation of cytotoxicity, analysis of DNA synthesis, and DNA fragmentation assays. One of the seven compounds tested showed signifi cant cytotoxicity in both cell lines and caused DNA degradation in the HT-29 cell line.

scholarly journals Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 10 ◽  
Author(s):  
Hehua Xiong ◽  
Jianxin Cheng ◽  
Jianqing Zhang ◽  
Qian Zhang ◽  
Zhen Xiao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Docking Simulation ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Mcf 7

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

scholarly journals Synthesis and Biological Evaluation of Novel Alkyl Amine Substituted Icariside II Derivatives as Potential Anticancer Agents

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2146 ◽  
Author(s):  
Tong Wu ◽  
Ting Li ◽  
Ya-Nan Kang ◽  
Li Liu ◽  
Xi-Man Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Anticancer Activity ◽  
Chain Length ◽  
Cell Lines ◽  
Hepatoma Cell ◽  
Biological Evaluation ◽  
Alkyl Amine ◽  
Icariside Ii ◽  
Mcf 7

A series of novel alkyl amine-substituted icariside II (ICA II) derivatives were synthesized by Mannich reactions at the 6-C position (compounds 4a–d) and changing the carbon chain length at the 7-OH position (compounds 7a–h), and their in vitro antitumor activity towards human breast cancer lines (MCF-7 and MDA-MB-231) and human hepatoma cell lines (HepG2 and HCCLM3-LUC) were evaluated by the MTT assay. Compared with ICA II, most of the twelve derivatives showed good micromole level activity and a preliminary structure-activity relationship (SAR) for the anticancer activity was obtained. Compound 7g showed the most potent inhibitory activity for the four cancer cell lines (13.28 μM for HCCLM3-LUC, 3.96 μM for HepG2, 2.44 μM for MCF-7 and 4.21 μM for MDA-MB-231), which was 2.94, 5.54, 12.56 and 7.72-fold stronger than that of ICA II. The preliminary SAR showed that the introduction of a alkyl amine substituent at 6-C was not favorable for the anticancer activity, while most of the 7-O-alkylamino derivatives exhibited good antitumor activity and the anticancer activity 7-O-alkylamino derivatives were influenced by the alkyl chain length and the different terminal amine substituents. Furthermore, the effects of compound 7g on apoptosis and cell cycle of MCF-7 cells were further investigated, which showed that compound 7g triggered apoptosis and arrested the cell cycle at the G0/G1 phase in MCF-7 cells. Our findings indicate that compound 7g may be a promising anticancer drug candidate lead.

Novel Pyrazolyl Benzoxazole Conjugates: Design, Synthesis, Molecular Docking Studies and in vitro Anticancer Activities

2019 ◽  
Vol 16 (8) ◽  
pp. 619-626
Author(s):  
Arunkumar Thiriveedhi ◽  
Ratnakaram Venkata Nadh ◽  
Navuluri Srinivasu ◽  
Narayana Murthy Ganta
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Docking Studies ◽  
Anticancer Activities ◽  
Molecular Docking Studies ◽  
Hybrid Molecules ◽  
Mcf 7

Nowadays, hybrid drugs have gained a significant role in the treatment of different health problems. Most of the hybrid molecules with different heterocyclic moieties were proved to be potent anti-tumor agents in cancer chemotherapy. Hence, the present study is aimed at the evaluation of in vitro anticancer activity of novel hybrid molecules (pyrazolyl benzoxazole conjugates) and to investigate their anticancer activity by molecular docking studies. Designed, synthesized and characterized the novel pyrazolyl benzoxazole conjugates. Anticancer activity of these compounds was determined by SRB assay. Then molecular docking studies were carried out against proto-oncogene tyrosine-protein kinase (ATP-Src, PDB: 2BDF), a putative target for cancer. All the synthesized compound derivatives were evaluated against MCF-7, KB, Hop62 and A549 cancer cell lines. Compounds 9b and 9c exhibited excellent anticancer activities with GI50 values of <0.1 µM against MCF-7 and A549 cell lines. Compound 9e exhibited good antitumor activity on MCF-7 and A-549 with GI50 values of 0.12 µM and 0.19 µM respectively. Compound 9g showed better anticancer activity on A-549 cancer cell line with GI50 of 0.34 µM. The two-hybrid molecules 9b and 9c are found to be comparably potent with the standard drug doxorubicin and may act as drug lead compounds in medicinal chemistry aspect. The present docking investigation proved that having benzoxazole of compound 9c at the position of benzofuran of reference compound (N-acetyl pyrazoline derivative) might be valid for contributing to anti-cancer activity.

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 of novel coumarin conjugated acetamides as promising anticancer agents: An in-silico and in-vitro approach.

2020 ◽  
Vol 20 ◽  
Author(s):  
Mamatha S. V ◽  
S. L. Belagali ◽  
Mahesh Bhat ◽  
Vijay M. Kumbar
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Mtt Assay ◽  
Anticancer Agents ◽  
In Silico ◽  
Active Sites ◽  
Biological Activities ◽  
Biological Evaluation ◽  
Mcf 7

Background: Coumarin and benzophenone possess a vast sphere of biological activities whereas thiazoles display various pharmacological properties. Hence we focused on incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity anticipating their interesting biological properties. Objective: The objective of the current work is synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. Methods: A novel series of Coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by multistep reaction sequence and were characterized by the FT-IR, LCMS and NMR spectral techniques. The newly synthesized compounds were screened for anticancer activity by in-silico and in-vitro methods. The cytotoxicity of the synthesized unique compounds had been executed for two different cancer cell lines MCF-7 (Breast cancer) and KB (Oral cancer) in comparison with standard paclitaxel by MTT assay. Results: The compound 7f is the potent motif with an acceptable range of IC 50 values for anticancer activity were 63.54 µg/ml and 55.67 µg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids MET 769, ARG 817 and LYS 721. Conclusion: Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.

Coumarin-substituted 1,2,4-triazole-derived silver(i) and gold(i) complexes: synthesis, characterization and anticancer studies

2019 ◽  
Vol 43 (3) ◽  
pp. 1216-1229 ◽  
Author(s):  
Gautam Achar ◽  
Shahini C. R. ◽  
Siddappa A. Patil ◽  
Jan Grzegorz Małecki ◽  
Srinivasa Budagumpi
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Carbene Complexes ◽  
Ht 29 ◽  
Mcf 7 ◽  
Triazolium Salts

A series of coumarin-substituted 1,2,4-triazolium salts and their respective silver– and gold– N-heterocyclic carbene complexes have been reported. The complexes displayed promising anticancer activity with GI50 values of up to 0.354 μM and 8.5983 μM against MCF 7 and HT-29 cell lines, respectively.

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