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

• Published in: Journal of natural products (Washington, D.C.) Vol. 82; no. 4; pp. 823 - 831
• Main Authors: Hamulić, Damir, Stadler, Marco, Hering, Steffen, Padrón, José M, Bassett, Rachel, Rivas, Fatima, Loza-Mejía, Marco A, Dea-Ayuela, M. Auxiliadora, González-Cardenete, Miguel A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 26-04-2019
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.8b00884

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 GABAA receptors (α1β2γ2s) 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.