Glucokinase-Activating Sesquinlignans from the Rhizomes of Acorus tatarinowii Schott

Abstract

Three novel sesquinlignans, tatanans A (1), B (2), and C (3), have been isolated from the rhizomes of Acorus tatarinowii Schott. Their structures were established by spectroscopic techniques and single-crystal X-ray analysis. Tatanans A-C potently increase GK enzymatic activity with EC(1.5) values in the range of 0.16-1.85 μM. The potent GK activity and unique structural features of tatanans make them promising leads for therapeutic development of antihyperglycemic drugs.

Enantioselective synthesis of tatanans A–C and reinvestigation of their glucokinase-activating properties

“…Methylation of the phenolic hydroxyl (NaH, CH 3 I, THF) followed by chemoselective hydrogenation of the terminal alkene in the presence of Lindlar’s catalyst delivered 26 mg of tatanan A (83% yield over two steps). Synthetic tatanan A showed identical spectroscopic data ( 1 H and 13 C NMR) to those published for the natural product; the optical rotation for the synthetic material was of the same sign but of a notably higher value (${false[\alpha false]}_D^{20}+55$ ( c 0.1, CH 3 OH); literature 6 ${false[\alpha false]}_D^{20}+10$ ( c 0.1, CH 3 OH)).…”

“…The first glucokinase activator was described in 2003 4 , and since that time pharmaceutical chemists have identified a variety of unique chemical scaffolds capable of stimulating glucokinase activity in vivo 5 . Although all glucokinase activators investigated to date are synthetic, the recent discovery of the tatanans, a novel class of naturally occurring lignan derivatives that reportedly possess potent glucokinase-activating capabilities, suggests that natural products might represent a rich resource for structurally and mechanistically new antidiabetic agents 6,7 . As a first step in exploring tatanans and the derivatives thereof as potential diabetes therapeutics, we undertook the total chemical synthesis and detailed mechanistic characterization of the glucokinase-activating properties of tatanans A, B and C.…”

“…Tatanans are structurally unique sesquilignans recently isolated from the ethyl acetate extracts of rhizomes of Acorus tatarinowii Schott plants 6 . Tatanan A incorporates three consecutive tertiary stereocentres and three aryl substituents appended to an acyclic framework.…”

Constituents and Activities of Acorus tatarinowii

“…Tatarinans T and S delayed the Aβ-induced paralysis in CL4176 transgenic C. elegans model at concentration of 100µM, in which tatarinan S exhibited the higher protective effect, with its PT 50 was 62.3% at 100µM and 30.8% at 10μM, respectively (Luo et al 2016). Tatanans A~C displayed potent and selective in vitro GK activity higher than positive control GKA22 (Ni et al 2011). …”

“…Tatanans A, B and C are novel sesquinlignans (Ni et al 2011), while tatarinan T is dimeric lignan with the rare C8-C7' linkage pattern (Luo et al 2016). …”