Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents
| Autor: | Hazem Elkady, Mohamed El-Zahabi, Helmy Sakr, Khaled El-Adl, Sally I. Eissa, Mohamed F. Zayed, Ibrahim H. Eissa, Adel S. Abdelraheem |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Vascular Endothelial Growth Factor A
Necrosis Antineoplastic Agents Pharmacology 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Cytotoxic T cell Humans Immunologic Factors Enzyme Inhibitors Molecular Biology Cell Proliferation Caspase 8 Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Tumor Necrosis Factor-alpha Organic Chemistry NF-kappa B Cell cycle In vitro 0104 chemical sciences Thalidomide Vascular endothelial growth factor 010404 medicinal & biomolecular chemistry chemistry Apoptosis Cell culture Drug Design medicine.symptom Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Bioorganic chemistry. 104 |
| ISSN: | 1090-2120 |
| Popis: | Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33h, 33i, 42f and 42h showed strong potencies against all tested cell lines with IC50 values ranging from 14.63 to 49.90 µM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33h and 42f showed a significant reduction in TNF-α. Furthermore, compounds 33i and 42f exhibited significant elevation in CASP8 levels. Compounds 33i and 42f inhibited VEGF. In addition, compound 42f showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42f, were performed. The results indicated that compound 42f significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase. |
| Databáze: | OpenAIRE |
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