Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition

Sahin Z., Biltekin S. N., YURTTAŞ L., BERK B., Ozhan Y., SİPAHİ H., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.212, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 212
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.ejmech.2020.113125
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database, Index Chemicus (IC)
  • Anahtar Kelimeler: Thiouracil, Thiocytosine, Adenosine, U87, Antitumor, Phosphosdiesterase, PDE, HEK293, MCF7, HETEROCYCLIC-COMPOUNDS, BIOLOGICAL EVALUATION, ANTITUMOR, AGONIST, DESIGN, TEMOZOLOMIDE, EXPRESSION, HYBRIDS, A(1), FEATURES
  • Anadolu Üniversitesi Adresli: Evet

Özet

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 mu M, which is slightly higher activity than cisplatin (1.67 mu M). The 11 most active compounds showed no signficant binding to adenosine A(1), A(2A) or A(2B) receptors at 1 mM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 mu M; 5f: 0.97 mu M). 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. (C) 2020 Elsevier Masson SAS. All rights reserved.