1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

• Published in: Chemistry & biodiversity 2021-08, Vol.18 (8), p.e2100261-n/a
• Main Authors: Gajić, Mihajlo, Ilić, Budimir S., Bondžić, Bojan P., Džambaski, Zdravko, Kojić, Vesna V., Jakimov, Dimitar S., Kocić, Gordana, Šmelcerović, Andrija
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell death; Cell lines; Cytotoxicity; Deoxyribonuclease; Deoxyribonuclease I; DNase I; enzyme inhibition; Inhibitors; Molecular docking; Molecular dynamics; Tetrahydroisoquinoline; Toxicity
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.202100261

Herein we report an assessment of 24 1,2,3,4‐tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 μM. The most potent was 1‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl)propan‐2‐one (2) (IC50=134.35±11.38 μM) exhibiting slightly better IC50 value compared to three other active compounds, 2‐[2‐(4‐fluorophenyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]‐1‐phenylethan‐1‐one (15) (IC50=147.51±14.87 μM), 2‐[2‐(4‐fluorophenyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]cyclohexan‐1‐one (18) (IC50=149.07±2.98 μM) and 2‐[6,7‐dimethoxy‐2‐(p‐tolyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]cyclohexan‐1‐one (22) (IC50=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC‐5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4‐tetrahydroisoquinoline‐based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.