Dihydrobenzofuran Neolignanamides: Lactase-Mediated Biomimetic Synthesis and Antiproliferative Activity

The biomimetic synthesis of a small library of dihydrobenzofuran neolignanamides (the natural trans-grossamide (4) and the related compounds 21-28) has been carried out through an eco-friendly oxidative coupling reaction mediated by Trametes versicolor lactase. These products, after complete spectroscopic characterization, were evaluated for their antiproliferative activity against Caco-2 (colon carcinoma), MCF-7 (mammary adenocarcinoma), and PC-3 (prostate cancer) human cells, using an MTT bioassay. The racemic neolignamides (+/-)-21 and (+/-)-27, in being the most lipophilic in the series, were potently active, with GI(50) values comparable to or even lower than that of the positive control 5-FU. The racemates were resolved through chiral HPLC, and the pure enantiomers were subjected to ECD measurements to establish their absolute configurations at C-2 and C-3. All enantiomers showed potent antiproliferative activity, with, in particular, a GI(50) value of 1.1 mu M obtained for (2R,3R)-21. The effect of (+/-)-21 on the Caco-2 cell cycle was evaluated by flow cytometry, and it was demonstrated that (+/-)-21 exerts its antiproliferative activity by inducing cell cycle arrest and apoptosis.