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.

Effective Pharmacophore for CDC25 Phosphatases Enzyme Inhibitors: Newly Synthesized Bromothiazolopyrimidine Derivatives

2020 ◽  
Vol 20 ◽  
Author(s):  
Mahmoud El-Shahat ◽  
Mowafia A.M. Salama ◽  
Ahmed F. El-Farargy ◽  
Mamdouh M. Ali ◽  
Dalia M. Ahmed
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Enzyme Inhibitors ◽  
Wide Spectrum ◽  
Hct116 Cell ◽  
Cytotoxic Activities ◽  
The Novel ◽  
Anticancer Activities ◽  
Starting Compound

Background: Thiazolopyrimidine analogues are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. Objective: To report the synthesis of novel bromothiazolopyrimidine derivatives and the study of both molecular modeling and in-vitro anticancer activity. Method: Novel bromothiazolopyrimidine derivatives 5–18 have been prepared from 2-bromo-3-(4-chlorophenyl)-1-(3,4- dimethylphenyl)-propenone 3 as a key starting compound. The anti-cancer activities of the new compounds were evaluated against HepG2, MCF-7, A549 and HCT116 cell lines. Results: The compounds 16, 17 and 18 showed cytotoxic and growth inhibitory activities on both colon and lung cells. The cytotoxic activities of the novel synthetic compounds 8, 9, 11, 16, 17 and 18 were due to CDC25 phosphatases inhibition as shown by the enzymatic binding assay. Although compounds 8, 9 and 11 have only demonstrated CDC25B phosphatases inhibition. Conclusion: The novel bromothiazolopyrimidine derivatives showed promising in vitro anticancer activities against colon cancer HCT116 and lung cancer A549 cell lines comparable to the anticancer drug doxorubicin.

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.

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.

Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

2020 ◽  
Vol 16 ◽  
Author(s):  
Délis Galvão Guimarães ◽  
Arlan de Assis Gonsalves ◽  
Larissa Araújo Rolim ◽  
Edigênia Cavalcante Araújo ◽  
Victória Laysna dos Anjos Santos ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Biological Activities ◽  
Supporting Electrolyte ◽  
Cancer Cell Lines ◽  
Molecular Structures ◽  
Cytotoxic Activities ◽  
Electrochemical Studies ◽  
Ic50 Values

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, then the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β-lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Method: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Result: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, being compounds 3 and 4 the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

scholarly journals ­Chemical profiling and biological activity of Peperomia blanda (Jacq.) Kunth

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4839 ◽  
Author(s):  
Wafa M. Al-Madhagi ◽  
Najihah Mohd Hashim ◽  
Nasser A. Awad Ali ◽  
Abeer A. Alhadi ◽  
Siti Nadiah Abdul Halim ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Radical Scavenging ◽  
Cancer Cell Lines ◽  
Cytotoxic Activities ◽  
Standard Drug ◽  
Chemical Profiling ◽  
First Time ◽  
Mcf 7

Background Peperomia belongs to the family of Piperaceae. It has different uses in folk medicine and contains rare compounds that have led to increased interest in this genus. Peperomia blanda (Jacq.) Kunth is used as an injury disinfectant by Yemeni people. In addition, the majority of Yemen’s population still depend on the traditional remedy for serious diseases such as cancer, inflammation and infection. Currently, there is a deficiency of scientific evidence with regards to the medicinal plants from Yemen. Therefore, this study was performed to assess the chemical profile and in vitro antioxidant and cytotoxic activities of P. blanda. Methods Chemical profiling of P. blanda was carried out using gas chromatography mass spectrometry (GCMS) followed by isolation of bioactive compounds by column chromatography. DPPH• and FRAP assays were used to evaluate antioxidant activity and the MTT assay was performed to estimate the cytotoxicity activity against three cancer cell lines, namely MCF-7, HL-60 and WEHI-3, and three normal cell lines, MCF10A, WRL-68 and HDFa. Results X-ray crystallographic data for peperomin A is reported for the first time here and N,N′-diphenethyloxamide was isolated for the first time from Peperomia blanda. Methanol and dichloromethane extracts showed high radical scavenging activity with an IC50 of 36.81 ± 0.09 µg/mL, followed by the dichloromethane extract at 61.78 ± 0.02 µg/mL, whereas the weak ferric reducing activity of P. blanda extracts ranging from 162.2 ± 0.80 to 381.5 ± 1.31 µg/mL were recorded. In addition, petroleum ether crude extract exhibited the highest cytotoxic activity against all the tested cancer cell lines with IC50 values of 9.54 ± 0.30, 4.30 ± 0.90 and 5.39 ± 0.34 µg/mL, respectively. Peperomin A and the isolated mixture of phytosterol (stigmasterol and β-sitosterol) exhibited cytotoxic activity against MCF-7 and WE-HI cell lines with an IC50 of (5.58 ± 0.47, 4.62 ± 0.03 µg/mL) and (8.94 ± 0.05, 9.84 ± 0.61 µg/mL), respectively, compared to a standard drug, taxol, that has IC50 values of 3.56 ± 0.34 and 1.90 ± 0.9 µg/mL, respectively. Conclusion The activities of P. blanda extracts and isolated compounds recorded in this study underlines the potential that makes this plant a valuable source for further study on anticancer and antioxidant activities.

scholarly journals Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines

Metabolomics ◽  
2021 ◽  
Vol 17 (12) ◽  
Author(s):  
Dorna Varshavi ◽  
Dorsa Varshavi ◽  
Nicola McCarthy ◽  
Kirill Veselkov ◽  
Hector C. Keun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Single Point ◽  
Hct116 Cell ◽  
Cellular Transformation ◽  
Single Copy ◽  
Driver Mutations ◽  
Glutathione Metabolism ◽  
Single Point Mutation

Abstract Introduction KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation. Objectives To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected. Methods Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRASG13D/+ HCT116 cell line and its isogenic, derivative cell lines KRAS+/– and KRASG13D/–. Results Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRASG13D/+ and KRASG13D/− cells have a distinct metabolic profile characterized by dysregulation of TCA cycle, up-regulation of glycolysis and glutathione metabolism pathway as well as increased glutamine uptake and acetate utilization. Conclusions Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS. Graphical abstract

scholarly journals Aspirin-Based Organoiron Dendrimers as Promising Anti-Inflammatory, Anticancer, and Antimicrobial Drugs

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1568
Author(s):  
Alaa S. Abd-El-Aziz ◽  
Maysun R. Benaaisha ◽  
Amani A. Abdelghani ◽  
Rabin Bissessur ◽  
Laila H. Abdel-Rahman ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Inflammatory Activity ◽  
Breast Cancer Cell Lines ◽  
Cell Viability Assay ◽  
Reference Drug ◽  
Anti Inflammatory

Designing nanocarriers with actions directed at a specific organ or tissue is a very promising strategy since it can significantly reduce the toxicity of a bioactive drug. In this study, an organometallic dendrimer was used to synthesize a biocompatible drug delivery system by attaching aspirin to the periphery of the dendrimer. Our goal is to enhance the bioavailability and anticancer activity of aspirin and reduce its toxicity through successive generations of organoiron dendrimers. The biological activity of aspirin-based dendrimer complexes was evaluated. The result of antimicrobial activity of the synthesized dendrimers also demonstrated an increase in their antimicrobial activity with increased generation of the dendrimers for most types of microorganisms. This study reveals for the first time that organoiron dendrimers linked with aspirin exhibit an excellent Gram-negative activity comparable to the reference drug Gentamicin. All synthesized dendrimers were tested for their anticancer activity against breast cancer cell lines (MCF-7), hepatocellular cell lines (Hep-G2), and a non-cancer cell line, Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, Doxorubicin. Compounds G3-D9-Asp and G4-D12-Asp exhibited noticeable activity against both cell lines, both of which were more effective than aspirin itself. In addition, the in vivo anti-inflammatory activity and histopathology of swollen paws showed that the designed aspirin-based dendrimers displayed significant anti-inflammatory activity; however, G2-D6-Asp showed the best anti-inflammatory activity, which was more potent than the reference drug aspirin during the same period. Moreover, the coupling of aspirin to the periphery of organoiron dendrimers showed a significant reduction in the toxicity of aspirin on the stomach.

Synthesis, In Silico and In Vivo Evaluation of Novel 1, 3, 4-Thiadiazole Analogues as Novel Anticancer Agents

2020 ◽  
Vol 17 (4) ◽  
pp. 434-444 ◽  
Author(s):  
Swathi Krishna ◽  
Byran Gowramma ◽  
Manal Mohammed ◽  
Rajagopal Kalirajan ◽  
Lakshman Kaviarasan ◽  
...  
Keyword(s):  
Vero Cell ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Binding Interaction ◽  
Standard Drug ◽  
Discovery Studio ◽  
Vero Cell Lines ◽  
Mcf 7

Background: 1,3,4-thiadiazole is a lead molécule which is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. Objective: The objective of the study was to synthesize series of 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine derivative and evaluated for their possible in vitro and in vivo anticancer activity. Methods: The synthesis of 2-aminonaphthoxy-1,3,4-thiadiazole and 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine as intermediates were carried out by cyclization method. A mixture of thiosemicarbazide and naphthoxyacetic acid/piperonylic acid and phosphoryl chloride were subjected to cyclization with phosphorous oxychloride to obtain compound 3. Further compounds 1 and 3 were reacted with different aromatic aldehydes in methanol to form compounds 2a-e and 4a-e. The compounds 2a-e and 4a-e were characterized for the melting points, IR, Proton NMR and Mass spectra. The compounds were further evaluated for their anticancer activity. The docking study was performed using Discovery studio 4.1 (Accelrys) software against DNA-binding domain of STAT3. The compounds were analyzed for the ligand-protein binding interaction(s) by molecular docking into the active site of STAT3β using the CDOCKER protocol of Discovery studio (v4.1). Results: The title compounds were screened for in vitro anticancer on human breastadenocarcinoma cells (MCF-7 and Vero). Compounds 4c, 4d and 2d against MCF 7 and 4d against Vero cell lines were found to be the most active dérivatives with IC50 values of 1.03, 2.81 and 3.45 µg/ml against MCF 7 and 31.81 µg/ml against Vero cell lines, respectively. Conclusion: From the in vivo anticancer studies, it was concluded that the synthesized compounds 4c and 4d displayed anticancer activity comparable to the standard drug, while the rest of the compounds demonstrated mild potency for anticancer studies.

Abstract 17064: Enrichment of Cardiotoxic Gene Expression Profile in Human Induced Pluripotent Stem-Cell Derived Cardiomyocytes in Response to Tyrosine Kinase Inhibitor Nilotinib

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Praful Aggarwal ◽  
Matthew White ◽  
Andrea Matter ◽  
Amy Turner ◽  
Benjamin Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
Gene Expression Profile ◽  
Cell Lines ◽  
Expression Profile ◽  
Molecular Mechanisms ◽  
P Value ◽  
Significant Differential Expression ◽  
Cell Index ◽  
Beat Rate

Small molecule tyrosine kinase inhibitors (TKIs) are a valuable class of therapeutics with widespread clinical utility against multiple cancers. However, there is strong evidence that TKIs are associated with cardiotoxicity and adverse cardiovascular events. Our understanding of the underlying mechanisms related to TKI induced cardiotoxicity is limited. Human iPSC derived cardiomyocytes (hiPSC-CMs) provide a flexible platform and unique model to study the underlying molecular mechanisms associated with TKI associated cardiotoxicity. In this study we describe the gene expression profile between hiPSC-CM cell lines which exhibit susceptibility vs. resistance. RNA-seq analysis was performed in hiPSC-CM cell lines from six participants in the NHLBI HyperGEN study (A to F). Experiments were performed in triplicate using sunitinib (SUN), vandetanib (VAN), gefitinib (GEF) and nilotinib (NIL). We analyzed beat rate, cell index and ATP viability as physiological measurements of CM toxicity and defined a 20% change from the normalized control as TKI susceptibility. Differential gene expression analysis was performed using DESeq2. We observed significant physiological differences between the different hiPSC-CMs after TKI treatment (beat rate, cell index and ATP viability). The most variable cell index and beat rate response was observed for NIL. Based on cell index, lines B, D, E were resistant while A, C, F were significantly more susceptible to NIL. Principal component analysis showed that the variance in gene expression was the highest after NIL treatment when compared to controls (16% for NIL; 11% for VAN; 6% for SUN and 5% for GEF). A total of 567 genes exhibited significant differential expression changes (adj. p-value ≤ 0.1) after NIL treatment in susceptible versus resistant lines. Pathway analysis showed significant enrichment for cardiotoxicity including pathways implicated in cardiac infarction, fibrosis, hypertrophy, and congestive cardiac failure. Taken together, our results identify unique gene expression changes associated with TKI cardiotoxicity. Furthermore, the variability in TKI susceptibility between different hiPSC-CM lines highlights the need to comprehensively assess cardiotoxicity in a diverse set of lines on a physiological and molecular level.

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