Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues

Abstract

The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs are reported. The compounds were generated from the readily available methyl callitrisate (7), which was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was conducted to determine the effects of the different functional groups present in these molecules, providing basic structure–activity relationship (SAR) elements. In particular, the ferruginol and sugiol analogs compounds 10–16 were characterized by the presence of a phenol moiety, higher oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. The biological profiling of these compounds was investigated against a panel of six human solid tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABAA) receptors (α1β2γ2s) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted.

Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

“… 15 Compounds 15b – 23b 25 were obtained in a similar manner, but in this case starting from (+)-methyl callitrisate ( 12 , R = 19-CO 2 Me) ( Scheme 1 ) extracted from Sandarac resin. 25 To generate the C-12 phenolic moiety, Friedel–Crafts and Baeyer–Villiger reactions were used ( Scheme 1 ). Functional group manipulation was carried out under standard conditions except for the hydrolysis of selected ester groups, which was executed by nucleophilic cleavage with LiI.…”

“…Based on our previous work, the tested compounds 12 – 26 were obtained following synthetic routes reported by us. ,− Compounds 12 – 14 and 24 – 26 were obtained from commercially available (−)-abietic acid as well as compounds 15a – 23a , whose intermediate was methyl dehydroabietate ( 12 , R = 18-CO 2 Me) (Scheme ) obtained from (−)-abietic acid by esterification and aromatization with a Pd/C catalyst . Compounds 15b – 23b were obtained in a similar manner, but in this case starting from (+)-methyl callitrisate ( 12 , R = 19-CO 2 Me) (Scheme ) extracted from Sandarac resin .…”

“…Based on our previous work, the tested compounds 12 – 26 were obtained following synthetic routes reported by us. ,− Compounds 12 – 14 and 24 – 26 were obtained from commercially available (−)-abietic acid as well as compounds 15a – 23a , whose intermediate was methyl dehydroabietate ( 12 , R = 18-CO 2 Me) (Scheme ) obtained from (−)-abietic acid by esterification and aromatization with a Pd/C catalyst . Compounds 15b – 23b were obtained in a similar manner, but in this case starting from (+)-methyl callitrisate ( 12 , R = 19-CO 2 Me) (Scheme ) extracted from Sandarac resin . To generate the C-12 phenolic moiety, Friedel–Crafts and Baeyer–Villiger reactions were used (Scheme ).…”

“…All compounds prepared in this work display spectroscopic data in agreement with the reported data. 8 , 15 , 23 − 25 Complete details of the optimized preparation of 6 are given in the Supporting Information . The purity of compounds was 95% or higher.…”

Abietane Diterpenoids from the Hairy Roots of Salvia corrugata

“…Abietane diterpenoids exhibit several interesting biological activities including antimicrobial, antifungal, anti-leishmanial, antiplasmodial, antiviral, antioxidant, antitumour, cytotoxic and anti-inflammatory activities [ 2 , 3 , 9 , 10 , 11 , 12 ]. Ferruginol is one of the most studied abietane diterpenoids and shows many of these important bioactivities [ 9 , 12 , 13 , 14 , 15 , 16 ]. The antiviral activity of this compound has been underlined [ 17 ], and interestingly against coronaviruses [ 18 , 19 ] i.e., SARS-CoV 3CL pro [ 19 , 20 ].…”