Thalidomide derivatives as nanomolar human neutrophil elastase inhibitors: Rational design, synthesis, antiproliferative activity and mechanism of action

by Selleckchem | Sep 27 2023

Here, we rationally designed a human neutrophil elastase (HNE) inhibitors 4a-4f derived from thalidomide. The HNE inhibition assay showed that synthesized compounds 4a, 4b, 4e and 4f demonstrated strong HNE inhibiton properties with IC50 values of 21.78-42.30 nM. Compounds 4a, 4c, 4d and 4f showed a competitive mode of action. The most potent compound 4f shows almost the same HNE inhibition as sivelestat. The molecular docking analysis revealed that the strongest interactions occur between the azetidine-2,4-dione group and the following three aminoacids: Ser195, Arg217 and His57. A high correlation between the binding energies and the experimentally determined IC50 values was also demonstrated. The study of antiproliferative activity against human T47D (breast carcinoma), RPMI 8226 (multiple myeloma), and A549 (non-small-cell lung carcinoma) revealed that designed compounds were more active compared to thalidomide, pomalidomide and lenalidomide used as the standard drugs. Additionally, the most active compound 4f derived from lenalidomide induces cell cycle arrest at the G2/M phase and apoptosis in T47D cells.

Comments:

That's impressive! It seems like you have conducted a rational design approach to develop human neutrophil elastase (HNE) inhibitors based on thalidomide. Here's a summary of the findings you mentioned:

1. Synthesized compounds 4a, 4b, 4e, and 4f exhibited strong HNE inhibition properties with IC50 values ranging from 21.78 to 42.30 nM. These compounds demonstrated potent inhibitory activity against HNE.

2. Compounds 4a, 4c, 4d, and 4f displayed a competitive mode of action, suggesting that they compete with the substrate for the active site of HNE.

3. The most potent compound, 4f, showed HNE inhibition comparable to that of sivelestat, which is a known HNE inhibitor used in clinical settings.

4. Molecular docking analysis revealed that the azetidine-2,4-dione group in the designed compounds formed strong interactions with three amino acids in the active site of HNE: Ser195, Arg217, and His57. These interactions likely contribute to the potent inhibitory activity.

5. The designed compounds were also evaluated for their antiproliferative activity against human T47D (breast carcinoma), RPMI 8226 (multiple myeloma), and A549 (non-small-cell lung carcinoma) cell lines. The compounds showed higher activity compared to thalidomide, pomalidomide, and lenalidomide, which were used as standard drugs in the study.

6. Compound 4f, which exhibited the highest potency, derived from lenalidomide, induced cell cycle arrest at the G2/M phase and apoptosis specifically in T47D cells, a breast carcinoma cell line.

Overall, your rational design approach led to the successful development of HNE inhibitors derived from thalidomide, with compound 4f showing remarkable inhibitory activity against HNE and promising antiproliferative effects against cancer cell lines.