Syntheses, antiproliferative activity and theoretical characterization of acitretin-type retinoids with changes in the lipophilic part

Acitretin analogs, incorporating changes in the lipophilic part, were efficiently synthesized from commercially available aromatic aldehydes or methyl ketones using the Wittig or Horner–Wadsworth–Emmons reaction. Their antiproliferative activity was evaluated against human breast MCF-7 epithelial cells. Analogs 3, 4, 8 and 11 exhibited strong, dose-dependent, antiproliferative activity on the tested cell line. Analog 3, incorporating three methoxy groups in the aromatic ring, exhibited the strongest inhibitory effect at 10 μM. High-level all electron conventional ab initio and density functional theory quantum chemical calculations were performed to obtain the molecular structure, electron charge distribution and polarization properties of all compounds of interest in this work. The most active analogs were planar and were characterized by larger dipole moments than the other synthesized molecules. Another factor of importance to the analysis of the activity of these molecules is the dipole polarizability.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights►Synthesis of acitretin analogs with changes in the lipophilic part. ►Assembly of polyene chain using Wittig-type olefination reactions. ►Certain analogs have stronger antiproliferative activity than acitretin. ►The structures of all compounds were calculated using ab initio methods. ►The most active inhibitor is planar and has the largest dipole moment.