Synthesis and biological evaluation of new chloro/acetoxy substituted isoindole analogues as new tyrosine kinase inhibitors

KÖSE A., Kaya M., Kishali N., AKDEMİR A., ŞAHİN E., KARA Y., ...Daha Fazla

BIOORGANIC CHEMISTRY, cilt.94, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 94
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.bioorg.2019.103421
  • Dergi Adı: BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Norcantharimides, Isoindole, Cytotoxicity, HeLa cells, ANTICANCER ACTIVITY, NORCANTHARIDIN ANALOGS, PROTEIN PHOSPHATASE-1, CONVENIENT SYNTHESIS, CANTHARIDIN, DERIVATIVES, MECHANISM
  • Atatürk Üniversitesi Adresli: Evet

Özet

We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac2O or Ac2O/AcCl in the presence of a catalytic amount of H2SO4 in order to yield new isoindole derivatives 8a-d and 9a-d. The anticancer activity of these compounds was evaluated against the HeLa cell lines. The synthesized compounds showed inhibitory effects on the viability of HeLa cells and the degree of cytotoxicity was increased with the level of bigger branched isoindole derivatives. To better understand the acting mechanism of these molecules, western blot analysis was performed with using mTOR and its downstream substrates. In addition, human mTOR and ribozomal S6 kinase beta 1 (RS6K beta 1) have been investigated with molecular modelling studies as possible targets for compound series 8 and 9.