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.
Highlights
Chemical diversity in natural products widely attracts scientific attention to find potential therapeutic agents like anticancer drugs from natural sources
The parasites, culture procedure and the activity of functionalized abietane analogs on Leishmania promastigotes were performed according to the method previously reported by us [28], while the intracellular amastigote assay was performed on L. amazonensis and L. infantum according to the fluorometric test [29]
We have carried out the first chemical synthesis of the abietane (+)-4epi-liquiditerpenoic acid A (8a)
Summary
Chemical diversity in natural products widely attracts scientific attention to find potential therapeutic agents like anticancer drugs from natural sources. Compounds 8a, 9, 13 and 16 are the most active agents in the antipromastigote assay (SI from >2 to >67) and could be good candidates for further research against the clinically relevant Leishmania amastigote forms It is noteworthy that sugiol analog 16 exhibited better activity against L. amazonensis (IC50 = 8.5 μM, SI > 23.5) and L. guyanensis (IC50 = 5.6 μM, SI > 35.7) parasites compared to the drug miltefosine, used as control It displayed a better selectivity index (SI = CC50/IC50) in those Leishmania spp. These ferruginol analogs were tested against L. infantum and L. amazonensis amastigotes (Table 2). N.C.: not calculated; e values taken from reference [23]
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