New cembrane-type diterpenoids from the South China Sea soft coral Sinularia crassa and their α-glucosidase inhibitory activity

Highlights

• Four new cembranoids were isolated from the soft coral Sinularia crassa.

• Providing solid proof to challenge the widely accepted B. Tursch’s empirical rule.

• (+)-2 and 5 were α-glucosidase inhibitors without cytotoxicity towards LO2 cells.

Abstract

A detailed chemical research of the soft coral Sinularia crassa collected from the South China Sea yielded a series of cembrane-type diterpenoids, including four new cembranoids, namely sinulacrassins A − C (1, (+)-2, (+)-4) and ent-xishaflavalin G ((+)-3), along with five known analogs ((-)-3, 5–8). Their structures were elucidated by detailed spectroscopic analysis, chemical methods, and the comparison with those literature data. The absolute configuration of 1 was established by time-dependent density functional theory electronic circular dichroism (TDDFT/ECD) calculation, and the absolute configuration of (+)-2 was determined using the modified Mosher's method. The bioassay results revealed that (+)-2 and 5 were novel α-glucosidase inhibitors with IC₅₀ values of 10.65 ± 0.16 and 30.31 ± 1.22 μM, respectively. In addition, (+)-2 and 5 were nontoxic towards human normal hepatocyte (LO2) cells at 100 μM. The present results highlighted the unusual coexistence of α and β configurations of C-1 in cembranoids from soft coral in the Order Alcyonacea, and provided new chemotype for the development of α-glucosidase inhibitors used in anti-diabetes treatment.

Introduction

Soft corals have been regarded as one of the most important marine sources of bioactive compounds, especially various fancy types of terpenoids, which makes them attractive targets for natural product chemists [1], [2], [3]. Soft corals belonging to the genus Sinularia (Phyulum Cnidaria, class Anthozoa, subclass Octocorallia, order Alcyonacea, family Alcyoniidae) are widely distributed in marine ecological systems. This genus has been well studied for its chemical constituents and biological activities, and especially the investigations on the Indian and Formosan soft coral S. crassa had resulted in the isolation of novel steroids and diterpenoids including cembranoids [4], [5], [6], [7]. The cembrane-type diterpenoids possess a 14-membered carbocyclic skeleton containing one isopropyl and three methyl groups with different degrees of oxidation that lead to a library of diverse analogs with structural features. However, due to the flexibility of the 14-membered macrocycle, the stereochemistry determination of cembranoids is still a very challenging task, especially for the absolute configuration of the C-1.

The previous research prompted us to persistently investigate the novel bioactive secondary metabolites from the soft coral S. crassa, and the present study on the soft coral S. crassa, collected from South China Sea for the first time, resulted in the isolation of four new cembranoids, sinulacrassins A (1), B ((+)-2), C ((+)-4), and ent-xishaflavalin G ((+)-3), along with five known analogs ((-)-3, 5–8) (Fig. 1). It is of interest to note that all these new compounds possess the unusual β configurations (absolute configuration) of iospropyl at C-1 that is very rare and somewhat surprising for the cembranoids derived from soft coral in the Order Alcyonacea. It is noteworthy that the discovery of the coexistence of α and β configurations of iospropyl at C-1 is very important since this true experimental fact solidly challenge the wildly accepted and applied empirical rule proposed by B. Tursch [8].

α-Glucosidase was considered as a key carbohydrate-hydrolase regulating blood glucose by specifically hydrolyzing 1,4-α-glucopyranosidic bond to produce α-glucose [9]. Early studies demonstrated that inhibition of α-glucosidase could retard the absorption of glucose and low the postprandial blood glucose levels [10]. Therefore, some well-known α-glucosidase inhibitors, such as acarbose, miglitol, and voglibose, have been developed as effective drugs in the treatment of type II diabetes [11]. However, the clinical application was limited by their unexpected adverse effects, including flatulence, diarrhoea, and stomachache. To discover new α-glucosidase inhibitors from marine source, some of isolated cembranoids were evaluated for in vitro α-glucosidase inhibitory activity, and the results showed compounds (+)-2 and 5 were new α-glucosidase inhibitors.

Herein, we report the isolation, structural elucidation of these new compounds and their α-glucosidase inhibitory and cytotoxicity evaluation as well.