Abstract
Four new derivatives of bioactive natural carnosic acid were obtained during a planned project of target synthesis starting from readily available natural products. In this work, we describe the synthesis of methyl 11,12-di-O-methyl-14-acetylcarnosate and methyl 11,12-di-O-methyl-14-formylcarnosate from methyl 11,12-di-O-methylcarnosate, which was obtained from commercial carnosic acid, by Friedel-Crafts acylation and formylation, respectively. Despite the low yield of the acylation reaction, 17% (56% brsm) yield, alternative formylation worked well which followed by Grignard addition and oxidation increased to 53% the overall yield of the 14-acetyl derivative. Subsequent selective 11-O-demethylation at low temperature afforded in high yield the corresponding hydroxy derivatives. The structure assignment of the newly synthesized compounds was established by 1H and 13C NMR, 2D-NMR and mass spectrometry. The proximity of the acetyl group at C14 to the characteristic isopropyl group of abietane-type diterpenes at C13 resulted in unusual signals in the 1H and 13C NMR spectra. These four novel compounds were screened in a panel of tumor cell lines and basic structure-activity relationships were deduced. They showed improved antiproliferative activity in comparison with natural carnosic acid, even in the low micromolar range for certain cells.