Azorellane diterpenoids from Laretia acaulis inhibit nuclear factor‐kappa B activity

Abstract

Transcription factor NF-kappaB plays a key role in the inducible expression of genes mediating proinflammatory effects, and is thus an important target for the development of antiinflammatory drugs. Laretia acaulis (Cav.) Gill et Hook (Apiaceae) is a medicinal plant used in the high Andes mountains for different ailments such as diabetes, inflammation and for general pain. In addition to the known azorellanol (2) and 7-deacetylazorellanol (4), 13-epiazorellanol (1) was also isolated from the aerial part of this plant. Its structure was based on spectroscopic comparison with azorellanol (2) and by chemical characterization. While compounds 2 and 4 showed potent anti-NF-kappaB activity by targeting the activity of the IkappaBalpha kinase, compound 1 was completely inactive highlighting the importance of position 13 in the biological activities of this class of tetracyclic diterpenoids.

Isolation of cytotoxic diterpenoids from the Chilean medicinal plantAzorella compactaPhil from the Atacama Desert by high-speed counter-current chromatography

“…By comparison of its spectroscopic data with the corresponding data of 13‐epi‐azorellanol ( 4 ) the structure of compound 3 (C 20 H 34 O 2 required m / z 306.2559; found, 306.2558) was assigned as 13‐epi‐7‐deacetyl‐azorellanol, which is the epimer at C‐13 of azorellanol ( 6 ). The structure of compound 3 (C 20 H 34 O 2 required m / z 306.2559; found, 306.2558) was assigned as 13‐epi‐7‐deacetyl‐azorellanol by comparison of its spectroscopic data with the corresponding data of 13‐epi‐azorellanol compound 4 , which is the epimer at C‐13 of azorellanol ( 6 ). Indeed, the lack of the signals in the 13 C and 1 H NMR spectra (170.9, 21.5 and 2.02 s) and the downfield shift of the signal for H‐7 at δ 3.96 (dd, J 7.1 and 11.3 Hz) in the 1 H NMR spectrum of 3 in comparison to the corresponding signal for 4 suggested the loss of the acetyl group at C‐7 in compound 3 .…”

“…The terpene partition (fractions I2–I3) was submitted to medium pressure silica‐gel (ø 30–60 µm) column (2.0 cm × 15 cm) and n ‐hexane/EtOAc 6:4 as solvent system, with a flow rate of 7 mL min −1 and afforded 4.0 mg of new compound 2 . Fraction II contained a polar mixture and was submitted to a medium‐pressure silica gel (ø 30–60 µm) column (2.5 cm × 25 cm) and n ‐hexane/EtOAc 7:3 as solvent system, flow 5 mL min −1 , yielding 10.3 mg of new compound 1 , 5.4 mg of compound 2 , 10.0 mg of compound 4 [13‐epi‐azorellanol, and 26.0 mg of compound 9 (13 α ,14 α ‐dihydroxymulin‐11‐en‐20‐oic acid)]. Fraction III afforded 12.0 mg of alpinum isoflavone and 3.5 mg of compound 6 (7‐deacetyl‐azorellanol), using medium pressure CC (2 cm × 15 cm) and the same solvent system.…”

“…This species is a well known source of diterpenoids with both mulinane and azorellane skeletons . These diterpenoids are very interesting since they have shown a variety of biological activities, including trypanosomicidal, trichomonocidal, gastroprotective, antiplasmodial, antibacterial, antiviral, spermicidal, cytotoxic, antihyperglycemic, anti‐tubercular, anti‐inflamatory and analgesic activities . The isolation of new substances from natural sources on a preparative or semi‐preparative scale is frequently necessary for further investigation of plant‐derived bioactive compounds.…”

Bioactive metabolites from the Andean flora. Antituberculosis activity of natural and semisynthetic azorellane and mulinane diterpenoids

“…1) (Loyola et al 1990a(Loyola et al , b, 1991(Loyola et al , 1996(Loyola et al , 1997a(Loyola et al , b, 1998(Loyola et al , 2002. These diterpenoids have displayed a wide variety of interesting biological activities, including antiprotozoal (Neira et al 1998;Loyola et al 2001aLoyola et al , b, 2004, antibacterial (Wächter et al 1999), antiviral (Abdel-Malek et al 1996, spermicidal (Morales et al 2003), cytotoxic (Mongelli et al 1997(Mongelli et al , 2000, antihyperglycemic (Fuentes et al 2005), antiinflammatory and analgesic (Delporte et al 2003;Bórquez et al 2007), and at least one mulinane diterpenoid, 9,12-cyclomulin-13-ol (1), has been reported as having antituberculosis activity (Wächter et al 1998). As a result of this, and as part of a project directed towards the search for natural antituberculosis agents, we have recently investigated the in vitro antituberculosis activity of a series of natural and semisynthetic azorellane and mulinane diterpenoids, when tested against two strains of Mycobacterium tuberculosis using the Alamar-blue assay (MolinaSalinas et al 2006(MolinaSalinas et al , 2010a.…”

7-6-5 Tricarbocyclic Diterpenes

“…Azorellanes [14,20,[38][39][40][41][42][43][44][45][46][47][48][49][50] These compounds do not present a functionalized C-20 but in C-13 is always present an oxygenated functionality. Mulinanes show a great variety of A. compacta Antibacterial [33] 11,14-Dioxo-mulin12en-20-oic acid, 47…”