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.

Crocetin inhibits invasiveness of MDA-MB-231 breast cancer cells via downregulation of matrix metalloproteinases.

Crocetin is a carotenoid dicarboxylic acid which, in nature, is esterified with glucose or gentiobiose units forming the crocins, abundant components of saffron (a spice with many reputed medicinal uses). We have previously reported that saffron, crocins and crocetin inhibit breast cancer cell proliferation. In order to further study the effect of crocetin on breast cancer cells, we used the highly invasive MDA-MB-231 cells and measured the viability with the WST-1 assay and the invasiveness through a reconstituted basement membrane. After 24 h incubation, crocetin significantly inhibited not only proliferation but also invasion at 1 and 10 µM. Cancer invasiveness and metastasis are associated with the expression of matrix metalloproteinases (MMPs). In order to study the molecular changes of MMP expression that might accompany the observed crocetin effects, gene expression of MMPs was studied by RT-PCR, whereas protein expression and gelatinolytic activity were determined with Western blotting and zymography, respectively. The gene and protein expression of pro-MT1-MMP and pro-MT2-MMP were greatly attenuated by both crocetin and all- TRANS-retinoic acid (ATRA, used as control). Incubation with 10 µM crocetin for 24 h in serum-free conditions reduced pro-MMP-9 activity and pro-MMP-2/MMP-2 protein levels. When cultured in media with sera 2 and 5 %, crocetin at 10 µΜ also reduced gelatinase activity. The above findings show that crocetin, the main metabolite of crocins, inhibits MDA-MB-231 cell invasiveness via downregulation of MMP expression.