New cembrane-type diterpenoids from the South China Sea soft coral Sinularia crassa and their α-glucosidase inhibitory activity
Graphical abstract
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.
Section snippets
Results
The frozen S. crassa were cut into pieces, and then exhaustively extracted by acetone under ultrasonic condition. The Et2O-soluble portion of the acetone extract was chromatographed repeatedly over silica gel, Sephadex LH-20, ODS and RP-HPLC, and chiral-HPLC to yield nine pure compounds (Fig. 1). Among them, five known compounds were readily identified as xishaflavalin G (-)-(3) [12], S-(+)-cembrane A (5) [13], (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4 (6) [14], (1R,3S,4S,7E,11E
Conclusion
In conclusion, four new cembranoids, namely sinulacrassins A-C (1, (+)-2, (+)-4), ent-xishaflavalin G ((+)-3), along with five known analogs ((-)-3, 5–8), were isolated and characterized from the soft coral S. crassa. The absolute configurations of 1 and (+)-2 was elucidated by TDDFT/ECD calculation and the modified Mosher's method, respectively. It is worth to point out that the determination of the configuration of isopropyl at C-1 of cembranoids has been being a challenging task. The B.
General experimental procedures
IR spectrum was recorded on a Nicolet iS50 spectrometer (Thermo Fisher Scientific, Madison, USA). Optical rotations were measured on a PerkinElmer 241MC polarimeter. CD&UV spectra were measured on a JASCO J-810 instrument. 1H and 13C NMR spectra were acquired on a Bruker AVANCE III 500 and 600 spectrometer. Chemical shifts are reported with the residual CHCl3 (δH 7.26 ppm; δC 77.16 ppm) as the internal standard for 1H and 13C NMR spectra. The LREIMS and HREIMS data were recorded on a
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This research work was financially supported by the National Key Research and Development Program of China (No. 2018YFC0310903), the Natural Science Foundation of China (Nos. 81991521, 81520108028, 21672230), the Drug Innovation Major Project (No. 2018ZX09711-001-001-009), the SKLDR/SIMM Project (No. SIMM1903ZZ-04).
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