Design, Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by 1H-NMR, 13C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC50 = 1.89 μM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.

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Design, Synthesis, Anti-Proliferative Evaluation and Cell Cycle Analysis of Hybrid 2-Quinolones

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190319142934 ◽

2019 ◽

Vol 19 (9) ◽

pp. 1132-1140

Author(s):

Heba A.E. Mohamed ◽

Hossa F. Al-Shareef

Keyword(s):

Cell Cycle ◽

Anticancer Agents ◽

Biological Activities ◽

Flow Cytometric Analysis ◽

Annexin V ◽

Cytotoxic Activities ◽

Significant Group ◽

Design Synthesis ◽

Standard Drug ◽

Wide Range

Background: Quinolones are a significant group of nitrogen heterocyclic compounds that exist in therapeutic agents, alkaloids, and synthetic small molecules that have important biological activities. A wide range of quinolones have been used as antituberculosis, antibacterial, anti-malarial, antifungal, anticonvulsant, anticancer agents and urease inhibitors. Methods: Ethyl 3,3-disubstituted-2-cyano propionates containing hybride quinolones derivatives were synthesized by the reaction of 1-amino-7-hydroxy-4-methylquinolin-2(1H)-one and its dibromo derivative with α, β-unsaturated carbonyl in ethanol. Results: A novel series of hybrid 2-quinolone derivatives was designed and synthesized. The compounds structures were confirmed using different spectroscopic methods and elemental analysis. The cytotoxic activities of all the compounds were assessed against HepG2 cell line in comparison with doxorubicin as a standard drug. Conclusion: Most compounds revealed superior anti-proliferative activity than the standard. Compound 4b, is the most active compound (IC50 = 0.39mM) compared with doxorubicin (IC50 = 9.23mM). DNA flow cytometric analysis of compound 4b showed cell cycle arrest at G2/M phase with a concomitant increase of cells in apoptotic phase. Dual annexin-V/ propidium iodide staining assay of compound 4b revealed that the selected candidate increased the apoptosis of HepG-2 cells more than control.

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Design, synthesis of novel quinazolinone-based oxobutanonitrile derivatives as antiproliferative agents targeting human breast cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211214104144 ◽

2021 ◽

Vol 21 ◽

Author(s):

Omaima Mohamed AboulWafa ◽

Hoda Mohamed Gamal El-Din Daabees ◽

Eman Salah Ezz-ElDien

Keyword(s):

Breast Cancer ◽

Binding Affinities ◽

Caspase 9 ◽

Design Synthesis ◽

Egfr Inhibition ◽

Cycle Arrest ◽

M Phase ◽

Quinazolinone Derivatives ◽

Mcf 7

Background: Breast cancer (BC) is among the leading causes of death among women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications. Objective: Novel quinazolinone-based oxobutanonitrile derivatives were designed, synthesized, and screened for in vitro anti-BC activity. Methods: The antiproliferative activities were determined using MTT assay against MCF-7 and MDA-MB-231 cell lines. EGFR, ARO, and caspase-9 enzymes were selected to explore the mechanism of action of the most potent compounds. Results: Tested compounds showed better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed with the most active compounds. The thienyl derivative 5 induced the greatest activation in caspase-9 level in treated MCF-7 breast cancer samples. The o-tolylhydrazone 3b, exhibiting promising ARO inhibition and weak EGFR inhibition, produced a noticeable high overexpression of caspase-9 and showed pre-G1 apoptosis and cell cycle arrest at G2/M phase for MCF-7 cells and at S-phase for MDA-MB-231 cells. Docking results revealed that 3b, elicited binding affinities to ARO comparable to those of letrozole. Conclusion: The obtained results support the therapeutic importance of some of these compounds as anti-BC agents in light of the simple methodology used for their synthesis. Their design offered a way for the optimization and development of apoptotic quinazolinone-based ARO and EGFR inhibitors.

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A Higher Frequency Administration of the Nontoxic Cycloartane-Type Triterpene Argentatin A Improved Its Anti-Tumor Activity

Molecules ◽

10.3390/molecules25081780 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1780 ◽

Cited By ~ 1

Author(s):

Zaira Tavarez-Santamaría ◽

Nadia J. Jacobo-Herrera ◽

Leticia Rocha-Zavaleta ◽

Alejandro Zentella-Dehesa ◽

Beatriz del Carmen Couder-García ◽

...

Keyword(s):

Waste Product ◽

Industrial Process ◽

Annexin V ◽

Control Group ◽

Healthy Control ◽

Hct 116 ◽

Hct 116 Cells ◽

Induced Apoptosis

Parthenium argentatum (Gray), commonly known as guayule, has been used to obtain natural rubber since the beginning of the 20th century. Additionally, the so called “resin” is a waste product derived from the industrial process. The cycloartane-type triterpene Argentatin A (AA) is one of the main constituents of the industrial waste resin. In this study we evaluated the AA anticancer activity both in vitro and in vivo in the HCT116 colon cancer cells. The apoptosis promotion of AA was assessed by the annexin V/propidium iodide (PI) assay. The senescence was evaluated for SA-β-galactosidase, and PCNA was used as a marker of proliferation. Its antitumor activity was evaluated using a xenograft mouse model. The results indicated that AA-induced apoptosis in HCT-116 cells and was positively stained for SA-β-galactosidase. In the xenografted mice test, the administration of AA at the dose of 250 mg/kg three times a week for 21 days reduced tumor growth by 78.1%. A comparable tumor reduction was achieved with cisplatin at the dose of 2 mg/kg administered three times a week for 21 days. However, nude mice treated with AA did not lose weight, as they did remarkably when treated with cisplatin. Furthermore, the animals treated with AA showed similar blood profiles as the healthy control group. These data indicate the low toxicity of AA compared to that shown by cisplatin.

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Design, Synthesis and Pharmacological Evaluation of Novel Imidazopyridine Analogues as Proton Pump Antagonist

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22433 ◽

2020 ◽

Vol 32 (4) ◽

pp. 776-782

Author(s):

Ravindra S. Sonawane ◽

Kiran D. Patil ◽

Avinash V. Patil

Keyword(s):

Spectral Analysis ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Inhibitory Activity ◽

Positive Control ◽

Docking Studies ◽

Design Synthesis ◽

Standard Drug ◽

Imidazopyridine Derivatives

A series of novel imidazopyridine derivatives as proton pump inhibitors was designed with compounds of CID data base and explored considering AZD0865 as standard. Many compounds were identified and docked in proton pump ATPase pocket (PDB ID: 4ux2). Molecular docking studies revealed that many compounds showed good proton pump ATPase inhibitory activity. The docking poses revealed the interaction of ligands with amino acid. The standard drug AZD0865 had docking score of -7.112302 and displayed interactions with Asn138 and Asp137. A series of novel imidazopyridine derivatives as proton pump inhibitors were docked, synthesized and characterized by IR, NMR, CHN and MS spectral analysis. The target imidazopyridines were prepared from substituted 2-aminonicotinic acid and 2-bromo-1-substituted ethanone. in vitro Studies explained that few compounds exhibited moderate to good proton pump ATPase inhibitory activity in comparison with the reference drugs i.e. AZD0865. Compounds 11 and 12 shown higher activities with the IC50 4.3. Compounds 1, 4, 6, 7, 8, 10 and 13 showed weak anti-ulcer activity with its IC50 5.2, 5.8, 5.5, 5.1, 4.9, 4.6 and 5.9 and positive control AZD0865 shown IC50 2.0.

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In Vitro Studies on the Immunomodulatory Effects of Pulicaria crispa Extract on Human THP-1 Monocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7574606 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Tarfa Albrahim ◽

Moonerah M. Alnasser ◽

Mashael R. Al-Anazi ◽

Muneera D. ALKahtani ◽

Saad Alkahtani ◽

...

Keyword(s):

Staining Method ◽

Inflammatory Diseases ◽

Annexin V ◽

Cytotoxic Activities ◽

Immunomodulatory Effects ◽

Macrophage Differentiation ◽

Future Studies ◽

Late Apoptosis ◽

Anti Inflammatory

Background. Pulicaria crispa (P. crispa) is a plant from the Compositae family that exhibits antioxidant, anti-inflammatory, antibacterial, and cytotoxic activities. Objective. The current study aimed at investigating the immunomodulatory effects of P. crispa extract in lipopolysaccharide- (LPS-) stimulated human monocytic THP-1 cells. Methods. To induce macrophage differentiation, THP-1 cell lines were treated with phorbol-12-myristate 13-acetate, followed by exposure to LPS with or without 50 or 100 μg/ml of P. crispa extract. The following tests were employed to test the immunomodulatory effects of the extract: MTT assay, ELISA, Western blotting analysis, cell migration and phagocytosis assays, and Annexin V staining method. Results. Exposure to 100 μg/ml P. crispa extract significantly reduced THP-1 cell proliferation, migration, and phagocytosis (in LPS-stimulated cells, but not in unstimulated cells). Moreover, the extract alone significantly reduced the rate of THP-1 cell apoptosis, while it increased the rate of late apoptosis. Molecular investigations showed that treatment with P. crispa extract significantly upregulated the expression of ERK1, p-MAPK, P-P38, and Bcl2, while it significantly reduced the expression of ERK5, Bax, NF-κB, P-NF-κB, CCL1, CCL2, CCL5, CCL22, CXCL1, and CXCL10. Conclusion. Pulicaria crispa extract exhibited anti-inflammatory, antiproliferative, antimigratory, and antiphagocytic effects in LPS-stimulated THP-1 cells. Future studies should investigate these mechanisms in animal models with chronic inflammatory diseases.

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Synthesis and Evaluation of Triazolyl Dihydropyrimidines as Potential Anticancer Agents

International Journal of Chemistry ◽

10.5539/ijc.v10n4p18 ◽

2018 ◽

Vol 10 (4) ◽

pp. 18

Author(s):

Rajanna Ajumeera ◽

Ganapathi Thipparapu ◽

Shireesha Boyapati ◽

Bharath Singh Padya ◽

Vijayalaxmi Venkatesan

Keyword(s):

Anticancer Agents ◽

Human Breast Cancer Cell ◽

S Phase ◽

Human Breast ◽

Standard Drug ◽

M Phase ◽

Ic50 Values ◽

Derivatives Of ◽

Mcf 7

Novel N – triazolyl 3(a-f) and O-triazolyl (4a-f) derivatives of 4, 6-diaryl-1, 4-dihydropyrimidines were synthesized through mannich reaction. All compounds were characterized by physical and spectral data. These compounds were screened for in vitro efficiency in human breast cancer cell (MCF-7&MDA-MB-231) lines and found to have very good anti-proliferative activity.  Among all compounds of 4b, 3e, 4e endowed with lesser respective IC50 values of 31.94, 55.73, 55.03 µM in MCF-7 cells and 41.50, 35.28, 32.06 µM in MDA-MB 231 cells by MTT assay. In further studies, Compounds 4b, 3e, 4e were found to arrest cell growth at S phase in MCF-7 cells. In MDA-MB 231 cells, 4b, 4e were found to arrest the cells in S phase, and compound 3e found to arrest G2/M phase when compared to the standard drug tamoxifen, arrested S phase in MCF-7 cells and G0/G1 phase in MDA-MB 231 cells.

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Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

Marine Drugs ◽

10.3390/md18040190 ◽

2020 ◽

Vol 18 (4) ◽

pp. 190 ◽

Cited By ~ 3

Author(s):

Wagdy M. Eldehna ◽

Ghada S. Hassan ◽

Sara T. Al-Rashood ◽

Hamad M. Alkahtani ◽

Abdulrahman A. Almehizia ◽

...

Keyword(s):

Breast Cancer ◽

Annexin V ◽

Fold Increase ◽

Biological Evaluation ◽

Design Synthesis ◽

Lead Compounds ◽

M Phase ◽

Indole Series ◽

Induced Apoptosis ◽

Mcf 7

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic spacer in the natural leads by a more flexible hydrazide linker while sparing the two peripheral indole rings. All the synthesized bis-indoles were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. The most potent congeners 7e and 9a against MCF-7 cells (IC50 = 0.44 ± 0.01 and 1.28 ± 0.04 μM, respectively) induced apoptosis in MCF-7 cells (23.7-, and 16.8-fold increase in the total apoptosis percentage) as evident by the externalization of plasma membrane phosphatidylserine detected by Annexin V-FITC/PI assay. This evidence was supported by the Bax/Bcl-2 ratio augmentation (18.65- and 11.1-fold compared to control) with a concomitant increase in the level of caspase-3 (11.7- and 9.5-fold) and p53 (15.4- and 11.75-fold). Both compounds arrested the cell cycle mainly in the G2/M phase. Furthermore, 7e and 9a displayed good selectivity toward tumor cells (S.I. = 38.7 and 18.3), upon testing of their cytotoxicity toward non-tumorigenic breast MCF-10A cells. Finally, compounds 7a, 7b, 7d, 7e, and 9a were examined for their plausible CDK2 inhibitory action. The obtained results (% inhibition range: 16%–58%) unveiled incompetence of the target bis-indoles to inhibit CDK2 significantly. Collectively, these results suggested that herein reported bis-indoles are good lead compounds for further optimization and development as potential efficient anti-breast cancer drugs.

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Design, Synthesis, SAR Study, Antimicrobial and Anticancer Evaluation of Novel 2-Mercaptobenzimidazole Azomethine Derivatives

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557518666180903151849 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1559-1571 ◽

Cited By ~ 6

Author(s):

Sumit Tahlan ◽

Balasubramanian Narasimhan ◽

Siong Meng Lim ◽

Kalavathy Ramasamy ◽

Vasudevan Mani ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Benzimidazole Derivatives ◽

Dilution Method ◽

Anticancer Activities ◽

Design Synthesis ◽

Standard Drug ◽

Wide Range ◽

Sar Study

Background: Various analogues of benzimidazole are found to be biologically and therapeutically potent against several ailments. Benzimidazole when attached with heterocyclic rings has shown wide range of potential activities. So, from the above provided facts, we altered benzimidazole derivatives so that more potent antagonists could be developed. In the search for a new category of antimicrobial and anticancer agents, novel azomethine of 2-mercaptobenzimidazole derived from 3-(2- (1H-benzo[d]imidazol-2-ylthio)acetamido)benzohydrazide were synthesized. Results and Discussion: The synthesized analogues were characterized by FT-IR, 1H/13C-NMR and MS studies as well C, H, N analysis. All synthesized compounds were evaluated for in vitro antibacterial activity against Gram-positive (B. subtilis), Gram-negative (E. coli, P. aeruginosa, K. pneumoniae and S. typhi) strains and in vitro antifungal activity against C. albicans and A. niger strains by serial dilution method, the minimum inhibitory concentration (MIC) described in μM/ml. The in vitro anticancer activity of synthesized compounds was determined against human colorectal carcinoma cell line (HCT- 116) using 5-fluorouracil as standard drug. Conclusion: In general, most of the synthesized derivatives exhibited significant antimicrobial and anticancer activities. Compounds 8, 10, 15, 16, 17, 20 and 22 showed significant antimicrobial activity towards tested bacterial and fungal strains and compound 26 exhibited significant anticancer activity.

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Celastrol Induced DNA Damage, Cell Cycle Arrest, and Apoptosis in Human Rheumatoid Fibroblast-Like Synovial Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x13500432 ◽

2013 ◽

Vol 41 (03) ◽

pp. 615-628 ◽

Cited By ~ 31

Author(s):

Zengtao Xu ◽

Guosheng Wu ◽

Xu Wei ◽

Xiuping Chen ◽

Yitao Wang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Inflammatory Diseases ◽

Annexin V ◽

Synovial Fibroblasts ◽

Damage Cell ◽

Cycle Arrest ◽

M Phase

Celastrol is one of the principal active ingredients of Tripterygium wilfordii Hook.f., a toxic Chinese medical herb traditionally prescribed for controlling pain and inhibiting inflammation in various chronic inflammatory diseases, including rheumatoid arthritis (RA). Resistance to apoptosis of fibroblast-like synoviocytes is considered a major characteristic of RA. In this study, we test celastrol's cytotoxic effect and potential mechanisms in human rheumatoid synovial fibroblasts (RA-FLS). In the cytotoxic assay, we found that celastrol dose-dependently decreased RA-FLS viability and increased LDH release. The apoptotic nuclear morphology was observed after celastrol treatment as determined by DAPI fluorescence staining. Flow cytometry analysis with PI and Annexin V revealed that celastrol induced RA-FLS cell cycle arrest in the G2/M phase and apoptosis. Furthermore, celastrol dramatically increased expression of Bax/Bcl-2, proteolytic cleavage of Caspase-3, -9, PARP, and decreased expression of FasR. In addition, celastrol treatment resulted in DNA damage. Collectively, we concluded that celastrol inhibits RA-FLS proliferation by inducing DNA damage, cell cycle arrest, and apoptosis in vitro, which might provide data for its application in RA treatment.

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