Molecular docking, synthesis, anticancer activity, and metabolomics study of boronic acid ester-containing fingolimod derivatives

DOYDUK D., DERKUŞ B., Sari B., EYLEM C. C., NEMUTLU E., YILDIRIR Y.

Archiv der Pharmazie, cilt.356, sa.12, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 356 Sayı: 12
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1002/ardp.202300382
  • Dergi Adı: Archiv der Pharmazie
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Anahtar Kelimeler: anticancer drugs, apoptosis, boron-containing drugs, cancer, fingolimod, CANCER, FTY720, METABOLISM, DESIGN
  • Ankara Üniversitesi Adresli: Evet

Özet

In recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques. The synthesized boron-containing drug candidates were found to significantly inhibit cell proliferation and induce apoptosis-mediated cell death in HT-29 (colorectal cells), SaOs-2 (osteosarcoma cells), and U87-MG (glioblastoma cells). Moreover, we revealed that the anticancer effects of boron-containing fingolimod compounds were found to be significantly enhanced over boron-free control groups and, strikingly, over the widely used anticancer drug 5-fluorouracil. The metabolomic analysis confirmed that administration of the boron-containing drug candidates induces significant changes in the metabolite profiles in HT-29, SaOs-2, and U87-MG cells. Altogether, our results showed that boron-containing fingolimod compounds can be further examined to reveal their potential as anticancer drug candidates.