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.

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 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.

scholarly journals Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2416 ◽  
Author(s):  
Abd Amr ◽  
Mohamed Abo-Ghalia ◽  
Gaber Moustafa ◽  
Mohamed Al-Omar ◽  
Eman Nossier ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inhibitory Activity ◽  
Active Sites ◽  
Kinase Inhibitors ◽  
Docking Studies ◽  
In Vitro Cytotoxicity ◽  
Binding Modes ◽  
Cytotoxicity Activity ◽  
Mcf 7

A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, 1H and 13C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC50 values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases.

scholarly journals Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

2021 ◽  
Vol 14 (2) ◽  
pp. 169
Author(s):  
Gloria Ana ◽  
Patrick M. Kelly ◽  
Azizah M. Malebari ◽  
Sara Noorani ◽  
Seema M. Nathwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Mitotic Catastrophe ◽  
Phase Cell ◽  
Computational Docking ◽  
Er Positive ◽  
Mcf 7

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

Design, Molecular docking, Synthesis and Biological evaluation of 5, 7 dimethyl pyrido(2, 3-d)pyrimidin-4-one and 4,5 dihydro pyrazolo (3, 4-d) pyrimidines for cytotoxic activity

2021 ◽  
pp. 3029-3038
Author(s):  
M. Sathish Kumar ◽  
M. Vijey Aanandhi
Keyword(s):  
Molecular Docking ◽  
Docking Simulation ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hep G2 ◽  
Molecular Docking Simulation ◽  
Hela Cell Lines ◽  
Benzene Diazonium ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

The fused pyrimidine derivatives are potent tyrosine kinase and thymidylate synthase inhibitors. The compound 3-(4-sulphonyl amino)-2-methyl thio-6-phenyl azo-5, 7-dimethyl pyrido(2,3-d)pyrimidin-4-one was synthesized from Ethyl 2-amino-4,6-dimethylpyridine-3-carboxylate, benzene diazonium chloride, benzene sulphonyl amino isothiocyanate in subsequent reactions. 1-(1, 3-benzothiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidines were synthesized from 1, 3-benzothiazole, 2-thiol, Hydrazine Hydrate, 2-hydrazinyl-1, 3-benzothiazole and aldehydes in subsequent reactions. Twenty-five derivatives pyrimidine scaffolds were designed and performed molecular docking studies for the ability to inhibit the target protein using molecular docking simulation, selective compounds were synthesized and characterized by spectral methods. All the synthesized compounds evaluated for their antioxidant activity and MTT assay exhibited compounds 13c, 13e and 14d can be potential anticancer candidates against MCF-7, Hep G2 and Hela cell lines respectively. Based on all the studies conclude that good agreement was observed between the top-ranked docking scores and top experimental inhibitors when compared with standards ascorbic acid and imatinib. Hence, the compounds could be considered as new anticancer hits for further lead optimization.

Evaluation of Benzamide-chalcone Derivatives as EGFR/CDK2 inhibitor: Synthesis, in-vitro Inhibition, and Molecular Modeling Studies

2021 ◽  
Vol 21 ◽  
Author(s):  
Akshada Joshi ◽  
Heena Bhojwani ◽  
Ojas Wagal ◽  
Khushboo Begwani ◽  
Urmila Joshi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Line ◽  
Antiproliferative Activity ◽  
Docking Studies ◽  
Wild Type ◽  
Chalcone Derivatives ◽  
Ht 29 ◽  
Egfr Kinase ◽  
Mcf 7 ◽  
Mutant Egfr

Background: EGFR (Epidermal Growth Factor Receptor) and CDK2 (Cyclin Dependent Kinase 2) are important targets in the treatment of many solid tumors and different ligands of these receptors share many common structural features. Objective: The study involved synthesis of benzamide-substituted chalcones and determination of their antiproliferative activity as well as preliminary evaluation of EGFR and CDK2 inhibitory potential using both receptor binding and computational methods. Methods: We synthesized 13 benzamide-substituted chalcone derivatives and tested their antiproliferative activity against MCF-7, HT-29 and U373MG cell-lines using Sulforhodamine B Assay. Four compounds were examined for activity against EGFR and CDK2 kinase. The compounds were docked into both EGFR and CDK2 using Glide software. The stability of the interactions for most active compound was evaluated by Molecular Dynamics Simulation using Desmond software. Molecular Docking studies on mutant EGFR (T790M, T790M/L858R, and T790M/C797S) were also carried out. Results: From the SRB assay, we concluded that compounds 1g, and 1k were effective in inhibiting the growth of MCF-7 cell line whereas the other compounds were moderately active. Most compounds were either moderately active or inactive on U373 MG and HT-29 cell line. Compounds 1g and 1k showed good inhibitory activity against CDK2 kinase while 1d and 1f were moderately active. Compounds 1d, 1f, 1g, and 1k were moderately active against EGFR kinase. Molecular docking reveals involvement of one hydrogen bond with Met793 in binding with EGFR however; it was not stable during simulation and these compounds bind to the receptor mainly via hydrophobic contacts. This fact also points towards a different orientation of the inhibitor within the active site of EGFR kinase. Binding mode analysis for CDK2 inhibition studies indicate that hydrogen bonding interaction with Lys 33 and Leu83 are important for the activity. These interactions were found to be stable throughout the simulation. Considering the results for wild-type EGFR inhibition, the docking studies on mutants were performed and which indicate that the compounds bind to the mutant EGFR but the amino acid residues involved are similar to the wild-type EGFR and therefore, the selectivity seems to be limited. Conclusion: These benzamide-substituted chalcone derivatives will be useful as lead molecules for the further development of newer inhibitors of EGFR and/or CDK2 kinases.

scholarly journals VANILLIN EXTRACTED FROM PROSO MILLET AND BARNYARD MILLET INDUCE APOPTOSIS IN HT-29 AND MCF-7 CELL LINE THROUGH MITOCHONDRIA MEDIATED PATHWAY

2017 ◽  
Vol 10 (12) ◽  
pp. 226 ◽  
Author(s):  
Deepa Priya Ramadoss ◽  
Nageswaran Sivalingam
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Barnyard Millet ◽  
Proso Millet ◽  
Ht 29 ◽  
Mcf 7

Objective: The main aim of the study was to investigate the bioactive compound vanillin extracted from proso millet (compound 1), and barnyard millet (compound 2) induces apoptotic cell death and whether it is mediated through mitochondrial pathway in HT-29 and MCF-7 cell line.Methods: The cells were treated with 250 μg/ml and 1000 μg/ml concentration of extracted vanillin for 48 hrs. Cytochrome c release and expression level of pro-apoptotic protein Bax and caspase-9 were detected by western blot analysis.Results: The results reveal that extracted compounds increased the release of cytochrome c and upregulating the expression of Bax and caspase-9 as concentration increases in a dose-dependent manner.Conclusion: The study suggests that the vanillin compound extracted from these millets induces apoptotic cell death through a mitochondria-dependent pathway.

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 Imines Structurally Related to Resveratrol as Dual Inhibitors of VEGF Protein Secretion and hTERT Gene Expression1

2017 ◽  
Vol 12 (5) ◽  
pp. 1934578X1701200
Author(s):  
Rosa Martí-Centelles ◽  
Juan Murga ◽  
Eva Falomir ◽  
Miguel Carda ◽  
J. Alberto Marco
Keyword(s):  
Tumor Cell ◽  
Tumor Cell Line ◽  
Biological Evaluation ◽  
Hek 293 ◽  
Htert Gene ◽  
Cytotoxic Compounds ◽  
Dual Inhibitors ◽  
Synthesis And Biological Evaluation ◽  
Ht 29 ◽  
Mcf 7

A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK-293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.

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