scholarly journals Cinnamamide-Chalcone Derivatives as CDK2 Inhibitors: Synthesis, Pharmacological Evaluation, and Molecular Modelling Study

2021 ◽  
Author(s):  
Akshada J. Joshi ◽  
Heena R. Bhojwani ◽  
Urmila Joshi ◽  
Khushboo V. Begwani ◽  
Ojas S. Wagal ◽  
...  
Keyword(s):  
Cell Line ◽  
Docking Studies ◽  
Hinge Region ◽  
Dynamics Simulation ◽  
Good Activity ◽  
Chalcone Derivatives ◽  
Excellent Activity ◽  
The Stability ◽  
Mcf 7

Abstract A series of 13 novel cinnamamide-chalcone derivatives (2a-2m) were synthesized and evaluated for their antiproliferative activity against MCF-7, K562, U373MG, and HT-29 cell lines by SRB assay. Considering the activities on MCF-7 cell line, eight compounds were tested for the in-vitro CDK2 inhibition and four (2g, 2h, 2k and 2l) were found to possess good activity (IC50<10µM). These four compounds were tested on EGFR kinase to assess the selectivity towards CDK2 and were found be nearly two times more selective. To corroborate the in-vitro enzyme assay data with binding, the compounds were docked into the CDK2 and EGFR using Glide software. The docking studies reveal that all eight compounds form hydrogen bonds with Lys33 (β-3 region) and Leu83 (hinge region) in CDK2 and the docking scores correlate well with the IC50 values. The most active compounds on CDK2 when docked in EGFR had lower docking scores. Only one compound interacts with Lys721 (β-3 region) and Met769 (hinge region). The stability of interactions with CDK2 was assessed for 2k and 2l by molecular dynamics simulation using Desmond software. In conclusion, three compounds possess excellent activity against MCF-7 cell line and good activity against CDK2.

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.

Guanidinyl and Amide Conjugated Benzothiazoles as Potential Anti- Tubercular Agent and their Cytotoxicity Study

2018 ◽  
Vol 16 (2) ◽  
pp. 121-128
Author(s):  
Mahesh Bhat ◽  
S.L. Belagali
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Positive Control ◽  
Docking Studies ◽  
Benzothiazole Derivatives ◽  
Excellent Activity ◽  
Ic50 Values ◽  
Tuberculosis Activity ◽  
Mcf 7

Background: Two series of Guanidinyl benzothiazole and benzothiazole diamide derivatives were synthesized and screened for their anti-mycobacterial activity and cytotoxicity on cancer cell lines. Methods: The anti-mycobacterium study indicates that all the synthesized benzothiazole compounds were appreciably active and some of the compounds have MIC values lower than the standard drugs. Benzothiazoleguanidinyl derivatives (13a, 13b and 13f) showed the excellent activity with MIC values 1.6 µg/mL. The guanidinyl group and electron donating group present in the molecule interacts with the microorganism and arrest the further growth, indicating excellent activity by these compounds. These benzothiazole derivatives were also tested for cytotoxicity against MCF-7 and KB Mouth cell lines by MTT assay and they were found to be moderately active. Results: For the KB-Mouth cell lines, diamide compounds (9a-9h) have remarkable activity and they showed IC50 values at 10 µg/mL. Compared to benzothiazole diamides, Benzothiazole guanidinyl compounds selectively acted as a good anti-mycobacterium agent. Conclusion: In order to rationalize the in-vitro anti-tuberculosis activity, we carried out molecular docking studies with enoyl acyl carrier reductase (InhA) of M. tuberculosis and they exhibited remarkable docking scores from -5.85 to -9.27, which was comparable with the positive control Isoniazid (INH) with -6.61 as the docking score and showed less affinity towards the DprE1 protiens.

scholarly journals Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1642
Author(s):  
Ulviye Acar Çevik ◽  
Betül Kaya Çavuşoğlu ◽  
Begüm Nurpelin Sağlık ◽  
Derya Osmaniye ◽  
Serkan Levent ◽  
...  
Keyword(s):  
Cell Line ◽  
Cancer Cell Line ◽  
Docking Studies ◽  
Binding Modes ◽  
Human Breast ◽  
Reference Drug ◽  
Anti Cancer ◽  
Estrogen Biosynthesis ◽  
Mcf 7

In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC50 = 0.032 ± 0.042 µM, compared to IC50 = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a–5p) were calculated by QikProp 4.8 software.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

Synthesis, Docking Study, Cytotoxicity, Antioxidant, and Anti-microbial Activities of Novel 2,4-Disubstituted Thiazoles Based on Phenothiazine

2020 ◽  
Vol 17 (2) ◽  
pp. 151-159
Author(s):  
Tran Nguyen Minh An ◽  
Pham Thai Phuong ◽  
Nguyen Minh Quang ◽  
Nguyen Van Son ◽  
Nguyen Van Cuong ◽  
...  
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Antimicrobial Activities ◽  
Significant Activity ◽  
Thiazole Derivatives ◽  
Ligand Interaction ◽  
Ic50 Value ◽  
Mcf 7

: A series of novel 1,3-thiazole derivatives (5a-i) with a modified phenothiazine moiety were synthesized and tested against cancer cell line MCF-7 for their cytotoxicity. Most of them (5a-i) were less cytotoxic or had no activity against MCF-7 cancer cell line. Material and Methods: The IC50 value of compound (4) was 33.84 μM. The compounds (5a-i) were also evaluated for antimicrobial activities, but no significant activity was observed. The antioxidant activity was conducted for target compounds (5a-i). The IC50 value of compound (5b) was 0.151mM. Results: The total amount of energy, ACE (atomic contact energy), energy of receptor (PDB: 5G5J), and ligand interaction of structure (4) were found to be 22.448 Kcal.mol-1 , -247.68, and -91.91 Kcal.mol-1, respectively. The structure (4) is well binded with the receptor because the values of binding energy, steric energy, and the number of hydrogen bondings are -91.91, 22.448 kcal.mol-1, and 2, respectively. It shows that structure (4) has good cytotoxicity with MCF-7 in vitro. Conclusion: The increasing of docking ability of structures (5a-i) with the receptor is presented in increasing order as (5f)>(5e)>(5g)>(5a)>(5b)>(5d)>(5c)>(5i)>(5h). The structure bearing substitution as thiosemicarbazone (4), nitrogen heterocyclic (5f), halogen (5e), and azide (5g) showed good cytotoxicity activity in vitro.

Design, Synthesis and In Vitro Anti-Cancer Evaluation of Novel Derivatives of 2-(2-Methyl-1,5-diaryl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3- yl)acetamide

2020 ◽  
Vol 16 (3) ◽  
pp. 340-349
Author(s):  
Ebrahim S. Moghadam ◽  
Farhad Saravani ◽  
Ernest Hamel ◽  
Zahra Shahsavari ◽  
Mohsen Alipour ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Peripheral Neuropathy ◽  
Cell Line ◽  
Normal Cell ◽  
Caspase 3 ◽  
Annexin V ◽  
Normal Cell Line ◽  
Anti Cancer ◽  
Mcf 7

Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. Methods: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100 μM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.

Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

2020 ◽  
Vol 20 (14) ◽  
pp. 1714-1721
Author(s):  
Hatem A. Abuelizz ◽  
El Hassane Anouar ◽  
Mohamed Marzouk ◽  
Mizaton H. Hasan ◽  
Siti R. Saleh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kojic Acid ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
New Class ◽  
Structure Activity ◽  
Tyrosinase Inhibitors ◽  
Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

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 Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection

2021 ◽  
Vol 9 (2) ◽  
pp. 402
Author(s):  
Hélène Michaux ◽  
Aymen Halouani ◽  
Charlotte Trussart ◽  
Chantal Renard ◽  
Hela Jaïdane ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Line ◽  
Thymic Epithelial Cells ◽  
Altered Expression ◽  
Coxsackievirus B4 ◽  
Gene Coding ◽  
Self Tolerance ◽  
Stat3 Phosphorylation ◽  
The Stability

Coxsackievirus B4 (CV-B4) can infect human and murine thymic epithelial cells (TECs). In a murine TEC cell line, CV-B4 can downregulate the transcription of the insulin-like growth factor 2 (Igf2) gene coding for the self-peptide of the insulin family. In this study, we show that CV-B4 infections of a murine TEC cell line decreased Igf2 P3 promoter activity by targeting a region near the transcription start site; however, the stability of Igf2 transcripts remained unchanged, indicating a regulation of Igf2 transcription. Furthermore, CV-B4 infections decreased STAT3 phosphorylation in vitro. We also showed that mice infected with CV-B4 had an altered expression of Igf2 isoforms as detected in TECs, followed by a decrease in the pro-IGF2 precursor in the thymus. Our study sheds new light on the intrathymic regulation of Igf2 transcription during CV-B4 infections and supports the hypothesis that a viral infection can disrupt central self-tolerance to insulin by decreasing Igf2 transcription in the thymic epithelium.

scholarly journals Synthesis and Experimental Validation of New Designed Heterocyclic Compounds with Antiproliferative Activity versus Breast Cancer Cell Lines MCF-7 and MDA-MB-231

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Vincenza Barresi ◽  
Carmela Bonaccorso ◽  
Domenico A. Cristaldi ◽  
Maria N. Modica ◽  
Nicolò Musso ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Cancer Cell Line ◽  
Breast Cancer Cell Lines ◽  
Design And Synthesis ◽  
Human Breast Cell ◽  
Mcf 7

Recent drug discovery efforts are highly focused towards identification, design, and synthesis of small molecules as anticancer agents. With this aim, we recently designed and synthesized novel compounds with high efficacy and specificity for the treatment of breast tumors. Based on the obtained results, we constructed a Volsurf+ (VS+) model using a dataset of 59 compounds able to predict the in vitro antitumor activity against MCF-7 cancer cell line for new derivatives. In the present paper, in order to further verify the robustness of this model, we report the results of the projection of more than 150 known molecules and 9 newly synthesized compounds. We predict their activity versus MCF-7 cell line and experimentally verify the in silico results for some promising chosen molecules in two human breast cell lines, MCF-7 and MDA-MB-231.

Sign in / Sign up

Export Citation Format

Share Document