Synthesis, in vitro cytotoxic and apoptotic effects, and molecular docking study of novel adamantane derivatives

Abstract

4-(Adamantane-1-carboxamido)-3-oxo-1-thia-4-azaspiro [4.4]nonan-2-yl]acetic acid (4a) and [4-(adamantane-1-carboxamido)-8-nonsubstituted/substituted-3-oxo-1-thia-4-azaspiro[4.5]decane-2-yl]acetic acid (4b-g) derivatives were synthesized; their structures were verified by elemental analysis, infrared spectroscopy, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectroscopy data; and their in vitro cytotoxicity activities were investigated against human hepatocellular carcinoma, human prostate adenocarcinoma, and human lung carcinoma cell lines (HepG2, PC-3, and A549, respectively), and a mouse fibroblast cell line (NIH/3T3). All compounds, except compound 4e, were found as cytotoxic, especially on A549 cells as compared with the other cells (selectivity index = 2.01-11.6). As a further step, the effects of compounds 4a-c on apoptosis induction were tested and the expression of selected apoptosis genes was analyzed. Among the selected compounds, compound 4a induced apoptosis remarkably.Moreover, computational calculations of the binding of compounds 4a-c to the BIR3 domain of the human inhibitor of apoptosis protein revealed ligand-protein interactions at the atomistic level and emphasized the importance of a hydrophobic moiety on the ligands for better binding.

Nascent pharmacological advancement in adamantane derivatives

“…Turk‐Erbul et al have synthesized a class of adamantane‐tethered thiazolidinedione hybrids and assayed their in vitro cytotoxicity activities toward several cancer cells using standard drug (doxorubicin). [ 51 ] Compound 6 exhibited high cytotoxicity against A549 cells. The effect of apoptosis induction was also checked in A549 cells.…”