Antiausterity Activity of Arctigenin Enantiomers: Importance of (2R,3R)-Absolute Configuration

Abstract

From a MeOH extract of powdered roots of Wikstroemia indica, six dibenzyl--butyrolactone-type lignans with (2S,3S)-absolute configuration [(+)-arctigenin (1), (+)-matairesinol (2), (+)-trachelogenin (3), (+)-nortrachelogenin (4), (+)-hinokinin (5), and (+)-kusunokinin (6)] were isolated, whereas three dibenzyl--butyrolactone-type lignans with (2R,3R)-absolute configuration [(-)-arctigenin (1*), (-)-matairesinol (2*), (-)-trachelogenin (3*)] were isolated from Trachelospermum asiaticum. The in vitro preferential cytotoxic activity of the nine compounds was evaluated against human pancreatic PANC-1 cancer cells in nutrient-deprived medium (NDM), but none of the six lignans (1-6) with (2S,3S)-absolute configuration showed preferential cytotoxicity. On the other hand, three lignans (1*-3*) with (2R,3R)-absolute configuration exhibited preferential cytotoxicity in a concentration-dependent manner with PC 50 values of 0.54, 6.82, and 5.85 M, respectively. Furthermore, the effect of (-)-and (+)-arctigenin was evaluated against the activation of Akt, which is a key process in the tolerance to nutrition starvation. Interestingly, only (-)-arctigenin (1*) strongly suppressed the activation of Akt. These results indicate that the (2R,3R)-absolute configuration of (-)-enantiomers should be required for the preferential cytotoxicity through the inhibition of Akt activation.

Phytochemistry, Pharmacology and Traditional Uses of Plants from the Genus Trachelospermum L.

“…These compounds which have the (2 R ,3 R )-absolute configuration exhibited preferential cytotoxicity compared with other lignan compounds in a concentration-dependent manner, with PC 50 values of 0.54, 6.82 and 5.85 μM, respectively [58]. Compound 111 , a new isoflavonoid glycoside, was isolated from the ethyl acetate extract of T. jasminoides , which was found to have the inhibitory activity against HepG2 and HL-60 cancer cells with IC 50 values of 131.5 and 58.2 μM, respectively [42].…”

Hinokinin, an Emerging Bioactive Lignan

“…Recently Awale et al studied the cytotoxicity of several lignans isolated from W. indica , against Panc-1 cancer cell line (human pancreatic cancer) [74]. They found that (8S,8′S)-(+)-hinokinin as well as other lignans, such as (+)-arctigenin, with the same stereochemistry, were inactive against Panc-1 cell line, whereas the (−) enantiomers were cytotoxic.…”

Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation

“…These structures comprise a γ-lactone core, with dibenzyl substitution at the C-8 and C-8’ positions in an anti-relationship [ 6 , 7 ]. Arctigenin possesses a range of biological activities and consequently has been well-studied to determine structure-activity relationships of its derivatives [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Results from previous studies have confirmed the lignan’s biological activities, with arctigenin analogues having cytotoxic, anti-tumour and hypoglycaemic activities, amongst others [ 10 , 12 , 13 , 14 ].…”

“…Arctigenin possesses a range of biological activities and consequently has been well-studied to determine structure-activity relationships of its derivatives [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Results from previous studies have confirmed the lignan’s biological activities, with arctigenin analogues having cytotoxic, anti-tumour and hypoglycaemic activities, amongst others [ 10 , 12 , 13 , 14 ]. Many of these derivatives have explored modifications of the aromatic rings, and to a slightly lesser extent the benzylic positions, [ 9 , 11 , 13 , 15 , 16 ], but there is a large underrepresentation of lactone ring modifications.…”