Anti-Angiogenic diketopiperazines from the Endophytic Fungus Diaporthe arecae Associated with Mangrove Kandelia obovate

Mangrove is littoral shrub distributes worldwide in subtropics and tropics. The mangrove ecosystem is a high humidity, high salinity, and hypoxia tolerant ecosystem which supports the existence of many halotolerant and halophilic microorganisms. Mangrove-derived endophytes are regarded as abundant sources of bioactive natural products and have aroused great interests of natural product chemists [1]. For instance, chamigrane sesquiterpenes isolated from basidiomycetous fungus showed cytotoxic effect against gastric cancer [2], while polyketides purified from Nectria sp. inhibited α-Glucosidase [3]. In our screening of Taiwanese mangrove-derived endophytes, twenty species of mangrove-derived endophytes were successfully purified and cultured. The EtOAc extracts of all isolated endophytes were evaluated for anti-cancer activity. As a result, the EtOAc extract of Diaporthe arecae isolated from mangrove Kandelia obovate was found to have potent cytotoxic activity against A549, HepG2, and MDA-MB-231 human cancer cell lines. Accordingly, a series of bioassay-guided fractionation for this endophyte was carried out. After repeated chromatography, twenty three diketopiperazines (1–23), were isolated from the culture broth of D. arecae. The structures of all isolateds were determined by their mass and NMR (COSY, HMBC, and HSQC) spectroscopic data. In the anti-angiogenic assay, cordysinin A (4) displayed mild inhibited effect by suppressing tube formation with IC₅₀ values of 15.2 µg/mL.

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[1] Xu J. RSC Adv 2015; 5: 841

[2] Choodej S, Teerawatananond T, Mitsunaga T, Pudhom K. Mar Drugs 2016; 14: 132

[3] Cui H, Liu Y, Nie Y, Liu Z, Chen S, Zhang Z, Lu Y, He L, Huang X, She Z. Mar Drugs 2016; 14: 86