Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition
| Autor: | Yağmur Özhan, Zhan-Guo Gao, Zafer Şahin, Leyla Yurttaş, Şeref Demirayak, Sevde Nur Biltekin, Barkın Berk, Hande Sipahi, Kenneth A. Jacobson |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adenosine
HEK293 Cell Survival Antineoplastic Agents PDE 01 natural sciences Article Thiouracil U87 03 medical and health sciences chemistry.chemical_compound Cytosine Structure-Activity Relationship Drug Discovery medicine Adenosine receptor binding Humans Receptor IC50 Cells Cultured 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Binding Sites Phosphosdiesterase Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry MCF7 Receptors Purinergic P1 Phosphodiesterase General Medicine Antitumor Adenosine receptor 0104 chemical sciences Cyclic Nucleotide Phosphodiesterases Type 4 chemistry Biochemistry Thiocytosine Phosphodiesterase 4 Inhibitors Pharmacophore Drug Screening Assays Antitumor Glioblastoma medicine.drug |
| Zdroj: | Eur J Med Chem |
| Popis: | Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 μM, which is slightly higher activity than cisplatin (1.67 μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 μM; 5f: 0.97 μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation. National Institute of Diabetes and Digestive and Kidney Diseases United States Department of Health & Human Services National Institutes of Health (NIH) - USA |
| Databáze: | OpenAIRE |
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