2. Academic Validation
  3. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents

Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents

  • Eur J Med Chem. 2019 Aug 15:176:117-128. doi: 10.1016/j.ejmech.2019.05.015.
Mohamed Hisham 1,  Bahaa G M Youssif 2,  Essam Eldin A Osman 3,  Alaa M Hayallah 4,  Mohamed Abdel-Aziz 5
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 2014, Saudi Arabia. Electronic address: bgyoussif@ju.edu.sa.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt.
  • 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt. Electronic address: abulnil@hotmail.com.
  • 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt.
PMID: 31108261 DOI: 10.1016/j.ejmech.2019.05.015
Abstract

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 μM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 μM. Compounds 18-20 and 22-24 increased the level of active Caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most Caspase-3 inducers. Compounds 22 and 23 increased the levels of Caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas Cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.

Keywords

Anti-proliferative; Apoptotic assay; EGFR; Hybrids; Oxime; Xanthine.

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