Design, Synthesis and Anticancer Activity of Site Specific Short Chain Cationic Peptide

2020 ◽  
Vol 17 (5) ◽  
pp. 631-646
Author(s):  
Ravi D. Sharma ◽  
Jainendra Jain ◽  
Ratan L. Khosa
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cyclic Peptide ◽  
Cyclic Compound ◽  
Chemotherapeutic Agents ◽  
Short Chain ◽  
Rational Approach ◽  
Phase Method ◽  
Host Defense Peptides ◽  
Cecropin A

Background: In spite of current progress in treatment methods, cancer is a major source of morbidity and death rate all over the world. Traditional chemotherapeutic agents aim to divide cancerous cells, are often associated with deleterious side effects to healthy cells and tissues. Host defense peptides Cecropin A and B obtained from insects are capable to lyses various types of human cancer cells at peptide concentrations which are not fatal to normal eukaryotic cells. Methods: In the present work we have designed short chain α-helical linear and cyclic peptide from cecropin A having same cationic charge, hydrophobicity and helicity. Synthesis of designed novel short chain linear (10) and cyclic compound (12) was accomplished by using solution phase method. All the coupling reactions were carried out by using dicyclohexylcarbodiimide (DCC) as the coupling reagent at room temperature in the presence of N-methylmorpholine (NMM) as the base. The Structure of newly synthesized peptidse were elucidated by 1H-NMR, 13C-NMR, FT-IR, FABMS and elemental analysis data.Cytotoxicity of synthesized compound was tested against Dalton’s Lymphoma Ascites (DLA), Ehrlich’s Ascites Carcinoma (EAC) and MCF-7 cell lines by using MTT assay and 5-FU as reference compound. Results: From biological assessment,it was found that short chain cyclicpeptide12 showed high level of cytotoxic activity against DLA and EAC cell lines. Conclusion: By utilizing a structure-based rational approach to anticancer peptide design from cecropin A, we were able to develop short chain linear and cyclic peptides having same charge, hydrophobicity and with improved activity. Systematically removing amino acids, we were able to retaining peptide charge and hydrophobicity/hydrophilicity in linear and cyclic peptide which results to optimize the anticancer activity against DLA and EAC cell lines.

Synthesis, Biological and Computational Evaluation of Novel 2,3-dihydro-2-aryl-4-(4- isobutylphenyl)-1,5-benzothiazepine Derivatives as Anticancer and Anti-EGFR Tyrosine Kinase Agents

2020 ◽  
Vol 20 (9) ◽  
pp. 1115-1128
Author(s):  
Afzal B. Shaik ◽  
Yejella R. Prasad ◽  
Srinath Nissankararao ◽  
Shaik Shahanaaz
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Side Effects ◽  
Tyrosine Kinase ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Receptor Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Chemotherapeutic Agents ◽  
Epidermal Growth

Background: Despite the availability of a variety of chemotherapeutic agents, cancer is still one of the leading causes of death worldwide because of the problems with existing chemotherapeutic agents like objectionable side effects, lack of selectivity, and resistance. Hence, there is an urgent need for the development of novel anticancer agents with high usefulness, fewer side effects, devoid of resistance and superior selectivity. Objective: The objective of this study is to synthesize a series of novel 1,5-benzothiazepine derivatives and evaluate their anticancer activity employing biological and computational methods. Methods: Twenty new benzothiazepines (BT1-BT20) were prepared by condensing different 1-(4- isobutylphenyl)ethanone chalcones with 2-amiothiophenol and evaluated for their anticancer activity by MTT assay against three cell lines including HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer). These compounds were also tested for their inhibitory action against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase enzyme by taking into account of their excellent action against colon and breast cancer cell lines. Further, the structural features responsible for the activity were identified by Pharmacophorebased modelling using Schrodinger’s PHASETM software. Results: Among the 20 benzothiazepine derivatives, three compounds viz., BT18, BT19 and BT20 exhibited promising activity against the cell lines tested and the activity of BT20 was more than the standard methotrexate. Again the above three compounds showed excellent inhibitory activity with the percentage inhibition of 64.5, 57.3 and 55.8 respectively against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase. PHASE identified a five-point AHHRR model for the proposed activity and the computational studies provided insights into the structural requirements for the anticancer activity and the results were consistent with the observed in vitro activity data. Conclusion: These novel benzothiazepines will be useful as lead molecules for the further development of new cancer therapies against colon and breast cancers.

Novel Tetrahydrobenzo [b] Thiophene Compounds Exhibit Anticancer Activity through Enhancing Apoptosis and Inhibiting Tyrosine Kinase

2019 ◽  
Vol 18 (12) ◽  
pp. 1761-1769 ◽  
Author(s):  
Souad A. El-Metwally ◽  
Ali K. Khalil ◽  
Abeer M. El-Naggar ◽  
Wael M. El-Sayed
Keyword(s):  
Tyrosine Kinase ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Hct116 Cell ◽  
Parent Compound ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Activities ◽  
Standard Drug ◽  
Reference Drug

Background: Developing new chemotherapeutic agents with molecular targets, larger margin of safety against normal cells and low cost is the target many scientists try to achieve. Objective: The present study was undertaken to investigate the anticancer activity of a novel series of thiophene compounds and the molecular mechanisms associated. Method: A series of novel heterocyclic compounds including pyrimidine derivatives (2, 3, 4, 5 8, 11, 12, 13, 14, and 15), thiophene derivatives (6, 7, and 10) and oxoisothiazolidine derivative (9) was synthesized from 4,5,6,7- tetrahydrobenzo[b] thiophene (1). The newly synthesized derivatives along with the parent compound were evaluated for their anticancer activity against human HepG2, MCF7 and HCT116 cell lines and compared to doxorubicin as a reference drug. Results: Compound 7 was very selective in targeting only the colon cells. Compounds 1, 5, and 12 showed strong cytotoxic activities against the 3 cell lines at 6-16 µM without any apparent toxicity to the normal fibroblasts WI-38. They had DNA affinity at 29-36 µM. The three compounds enhanced apoptosis to varying degrees elevating the expression of Bax, caspase 9 and caspase 3 in HepG2. Compound 5 was the most potent analogue and was superior to the standard drug used in upregulating the apoptotic genes and inhibiting tyrosine kinase at 1 µM. The IC50 value for compound 5 against TK was 296 nM. Conclusion: Taken together, this study presents some thiophene scaffolds as auspicious hits for further optimization as specific antiproliferative agents against cancer cells and promising tyrosine kinase inhibitors at nanomolar concentrations.

scholarly journals Modulation of Butyrate Anticancer Activity by Solid Lipid Nanoparticle Delivery: An in Vitro Investigation on Human Breast Cancer and Leukemia Cell Lines

2014 ◽  
Vol 17 (2) ◽  
pp. 231 ◽  
Author(s):  
Federica Foglietta ◽  
Loredana Serpe ◽  
Roberto Canaparo ◽  
Nicoletta Vivenza ◽  
Giovanna Riccio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Solid Lipid Nanoparticles ◽  
Target Genes ◽  
Lipid Nanoparticles ◽  
Short Chain ◽  
Solid Lipid ◽  
Mcf 7

Purpose. Histone modification has emerged as a promising approach to cancer therapy. The short-chain fatty acid, butyric acid, a histone deacetylase (HD) inhibitor, has shown anticancer activity. Butyrate transcriptional activation is indeed able to withdraw cancer cells from the cell cycle, leading to programmed cell death. Since butyrate’s clinical use is hampered by unfavorable pharmacokinetic and pharmacodynamic properties, delivery systems, such as solid lipid nanoparticles (SLN), have been developed to overcome these constraints. Methods. In order to outline the influence of butyrate delivery on its anticancer activity, the effects of butyrate as a free (sodium butyrate, NB) or nanoparticle (cholesteryl butyrate solid lipid nanoparticles, CBSLN) formulation on the growth of different human cancer cell lines, such as the promyelocytic leukemia, HL-60, and the breast cancer, MCF-7 was investigated. A detailed investigation into the mechanism of the induced cytotoxicity was also carried out, with a special focus on the modulation of HD and cyclin-dependent kinase (CDK) mRNA gene expression by real time PCR analysis. Results. In HL-60 cells, CBSLN induced a higher and prolonged expression level of the butyrate target genes at lower concentrations than NB. This led to a significant decrease in cell proliferation, along with considerable apoptosis, cell cycle block in the G0/G1 phase, significant inhibition of total HD activity and overexpression of the p21 protein. Conversely, in MCF-7 cells, CBSLN did not enhance the level of expression of the butyrate target genes, leading to the same anticancer activity as that of NB. Conclusions. Solid lipid nanoparticles were able to improve butyrate anticancer activity in HL-60, but not in MCF-7 cells. This is consistent with difference in properties of the cells under study, such as expression of the TP53 tumor suppressor, or the transporter for short-chain fatty acids, SLC5A8. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.Purpose. Histone modification has emerged as a promising approach to cancer therapy. The short-chain fatty acid, butyric acid, a histone deacetylase (HD) inhibitor, has shown anticancer activity. Butyrate transcriptional activation is indeed able to withdraw cancer cells from the cell cycle, leading to programmed cell death. Since butyrate’s clinical use is hampered by unfavorable pharmacological pharmacokinetic and pharmacodynamicproperties, delivery systems, such as solid lipid nanoparticles (SLN), have been developed to overcome these constraints. Methods. In order to outline the influence of butyrate delivery on its anticancer activity, the effects of butyrate as a free (sodium butyrate, NB) or nanoparticle (cholesteryl butyrate solid lipid nanoparticles, CBSLN) formulation was investigated on the growth of different human cancer cell lines, such as the promyelocytic leukemia, HL-60, and the breast cancer, MCF-7 was investigated. A detailed investigation into the mechanism of the induced cytotoxicity was also carried out, with a special focus on the modulation of HD and cyclin-dependent kinase (CDK) mRNA gene expression by real time PCR analysis. Results. In HL-60 cells, CBSLN induced a higher and prolonged expression level of the butyrate target genes at lower concentrations than NB. This led to a significant decrease in cell proliferation, along with considerable apoptosis, cell cycle block in the G0/G1 phase, significant inhibition of total HD activity and overexpression of the p21 protein. Conversely, in MCF-7 cells, CBSLN did not enhance the level of expression of the butyrate target genes, leading to the same anticancer activity as that of NB. Conclusions. Solid lipid nanoparticles were able to improve butyrate anticancer activity in HL-60, but not in MCF-7 cells. This is consistent with the difference in cells’ properties of the cells under study, such as expression of the TP53 tumor suppressor, or the transporter for short-chain fatty acids, SLC5A8. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. <w:LsdException Locked="false"

Anticancer Activity of Diosgenin and its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis

2021 ◽  
Vol 21 ◽  
Author(s):  
Nivedita Bhardwaj ◽  
Nancy Tripathi ◽  
Bharat Goel ◽  
Shreyans K. Jain
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Anticancer Activity ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Rational Approach ◽  
Potential Candidate ◽  
Potential Implication ◽  
Apoptosis Protein ◽  
Synthetic Derivatives

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations

2019 ◽  
Vol 19 (11) ◽  
pp. 914-926 ◽  
Author(s):  
Maiara Bernardes Marques ◽  
Michael González-Durruthy ◽  
Bruna Félix da Silva Nornberg ◽  
Bruno Rodrigues Oliveira ◽  
Daniela Volcan Almeida ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Cell Lines ◽  
Chemotherapeutic Agents ◽  
Atp Binding ◽  
Human Leukemia ◽  
Atp Binding Site ◽  
Mechanistic Insight ◽  
Multiple Drugs

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

Extraction, Chemical Composition, Antioxidant Property and In vitro Anticancer Activity of Silymarin from Silybum Marianum On Kb and A549 Cell Lines

2020 ◽  
Vol 17 ◽  
Author(s):  
Mojgan Azadpour ◽  
Mohammad Mehdi Farajollahi ◽  
Ali Mohammad Varzi ◽  
Pejman Hashemzadeh ◽  
Hossein Mahmoudvand ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
A549 Cell ◽  
Hplc Analysis ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Antioxidant Property ◽  
Silybum Marianum ◽  
Stable Free Radical

Introduction: This study aimed to evaluate the antioxidant property of silymarin (SM) extracted from the seed of Silybum marianum and its anticancer activity on KB and A549 cell lines following 24, 48, and 72 h of treatment. Methods: Ten grams of powdered S. marianum seeds were defatted using n-hexane for 6 hours and then extracted by methanol. The silymarin extracted of extraction components The extracted components of silymarin were measured by spectrophotometric assay and HPLC analysis. 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, phenol content, total flavonoid content, and total antioxidant capacity were measured to detect the antioxidant properties of SM. The anticancer activity of the SM on cell lines evaluated by MTT. Results: In HPLC analysis, more than 50% of the peaks were related to silibin A and B. SM was reducedDPPH (the stable free radical) with a 50% inhibitory concentration (IC50) of 6.56 μg/ ml in comparison with butylated hydroxyl toluene (BHT), which indicated an IC50 of ~3.9 μg/ ml.The cytotoxicity effect of SM on the cell lines was studied by MTT assay. The cytotoxicity effect of the extracted silymarin on KB and A549 cell lines was observed up to 80 and 70% at 156 and 78 µg/ml, respectively. The IC50 value of the extracted SM on KB and A549 cell lines after 24 hours of treatment was seen at 555 and 511 µg/ml, respectively. Conclusion: Due to the good antioxidant and anticancer properties of the isolated silymarin, its use as an anticancer drug is suggested.

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