Synthesis, Absolute Configuration, Biological Profile and Antiproliferative Activity of New 3,5-Disubstituted Hydantoins
Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hyd...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Book |
| Published: |
MDPI AG,
2024-09-01T00:00:00Z.
|
| Subjects: | |
| Online Access: | Connect to this object online. |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives <b>5a</b>-<b>i</b> were prepared as racemic mixtures of <i>syn</i>- and <i>anti</i>-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of <i>syn</i>-<b>5a</b> and <i>anti</i>-hydantoins <b>5b</b> were separated by preparative high-performance liquid chromatography (HPLC) using <i>n</i>-hexane/2-propanol (90/10, <i>v</i>/<i>v</i>) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers <b>5a</b> was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated <i>in vitro</i> against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound <i>anti</i>-<b>5c</b> showed potent cytotoxic activity against the human tumor cell line MCF7 (IC<sub>50</sub> = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC<sub>50</sub> = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity. |
|---|---|
| Item Description: | 10.3390/ph17101259 1424-8247 |