Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities

OSMANİYE D., KORKUT ÇELİKATEŞ B., SAĞLIK B. N., LEVENT S., ACAR ÇEVİK U., ÇAVUŞOĞLU B. K., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.210, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 210
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.ejmech.2020.112979
  • 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: Benzoxazole, Piperazine, Phortress, Anticancer, CYP1A1, ANTITUMOR BENZOTHIAZOLES, IN-VITRO, INHIBITORY-ACTIVITY, AMIDE MOIETY, DNA-DAMAGE, 2-(4-AMINOPHENYL)BENZOTHIAZOLES, POTENT, 2-(4-AMINO-3-METHYLPHENYL)BENZOTHIAZOLE, PRODRUGS, AGENTS
  • Anadolu Üniversitesi Adresli: Evet

Özet

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, H-1 NMR, C-13 NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress. (C) 2020 Elsevier Masson SAS. All rights reserved.