Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) ( 7 ) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate ( 8 ), which was derived from (−)-abietic acid ( 1 ). Biological comparison was conducted according to the different functional groups, leading to some basic structure–activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10 – 16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis ). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABA A receptors (α 1 β 2 γ 2s ) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.