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

Abstract

similar chemistry. The combined findings indicate that these abietane-diterpenoid natural product analogues offer a source of novel bioactive molecules with promising pharmacological and drug-likeness properties. ASSOCIATED CONTENT Supporting Information Available: Complete experimental details for the synthesis of compounds 7 and 9-16, including copies of 1 H NMR and 13 C NMR spectra, and for all the biological assays. A list with the complete results of the docking studies carried out on the analyzed targets and SMILES codes is also available in the S.I.

Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues

“…Furthermore, after comparing antipromastigote activity of synthetic lambertic acid (13) (IC50 values from 12.8 to 51.5 μM) with the corresponding 12-hydroxydehydroabietic acid (IC50 values from 43.6 to 71.4 μM, ref. [17]), both superior potency and SI (2.5-fold less cytotoxic) were recorded. It is also important to highlight that the methyl ester of liquiditerpenoic acid A, under the experimental conditions, had solubility problems and was not tested.…”

“…It is interesting to note that 4-epi-liquiditerpenoic acid A (8a) displayed activity in the tested promastigote Leishmania spp. strains, particularly, remarkable activity was observed against L. guyanensis while (+)-liquiditerpenoic acid A (8b, Figure 1) was inactive [17]. While no C19-functionalized derivative showed better potency than the reference drug (miltefosine) for L. donovani, it was gratifying to observe improved activity for the C18-congeners.…”

“…One clear SAR that can be established is that oxidation at C-7 results in less potent molecules for esters and alcohols (Table 4, compounds 12 and 14 vs. 16 and 15, respectively). On comparing with the corresponding C18-functionalized equivalents [17], in general, the C19-functionalized series is more potent. In particular, the corresponding C18-functionalized analogs of compounds 8a, 13, 14 and 16 were less potent for all tested cell lines.…”

“…On comparing these antileishmanial results with those of the corresponding C18functionalized equivalents (see ref. [17]), some structure-activity relationships could be established. Overall, it can be deduced that the C19-functionalized derivatives are less cytotoxic on J774 cells.…”

“…In addition, dehydroabietic acid (3) from Boswellia thurifera resin has been reported as a positive gamma-aminobutyric acid type A (GABAA) receptor modulator [16]. Recently, we reported on the synthesis and biological activity of (+)-liquiditerpenoic acid A or abietopinoic acid [17]. In that work, we synthesized and studied biologically (antitumor, GABAA modulation and antileishmanial) a series of ferruginol analogs functionalized at C-18 from (-)-abietic acid via methyl dehydroabietate (C-4 epimeric compounds of those depicted in Scheme 1).…”