Bromotyrosine alkaloids with acetylcholinesterase inhibitory activity from the Thai sponge Acanthodendrilla sp.

Twenty-one bromotyrosine alkaloids, including two new compounds, 13-oxosubereamolline D (5) and acanthodendrilline (21), were isolated from the MeOH crude extract of the Thai sponge Acanthodendrilla sp. collected from Koh-Ha Island, Krabi, Thailand [1, 2]. Their structures were determined by several spectroscopic techniques involving 1D- and 2D-NMR, high-resolution mass, in conjugation with optical rotation and circular dichroism data. Importantly, our result is the first report of the discovery of bromotyrosine alkaloids from the sponge belonging to the order Dendroceratida [1]. In addition, the S and R synthetic enantiomers of 21 were prepared to resolve the absolute configuration of its single chiral carbon at oxazolidone moiety. Both enantiomers of 21 were obtained from the 4-step synthetic strategy using tyramine as a precursor [2].

All isolated compounds were evaluated for the inhibitory activities against electric eel acetylcholinesterase (EeAChE) and human recombinant acetylcholinesterase (hrAChE) by the modified Ellman's method [3]. The results indicated that homoaerothionin (7) exhibited the strongest inhibitory activity with IC₅₀s of 2.9 and 4.5µM against EeAChE and hrAChE, respectively. The hrAChE inhibition kinetics of 7 showed increased K _m and unchanged V _max values, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and specific length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease.

Acknowledgements: The Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0276/2552) is acknowledged for financial support.

Keywords: Bromotyrosine alkaloids, acetylcholinesterase inhibitor, sponge, Acanthodendrilla.

References:

[1] Sirimangkalakitti N, Olatunji O, Changwichit K, Saesong T, Chamni S, Chanvorachote P, Ingkaninan K, Plubrukarn A. Suwanborirux K. Bromotyrosine marine alkaloids with acetylcholinesterase inhibitory activity from the Thai sponge Acanthodendrilla sp. Nat Prod Commun 2015; 10: 1945 – 1949

[2] Sirimangkalakitti N, Yokoya M, Chamni S, Chanvorachote P, Plubrukrn A, Saito N, Suwanborirux K. Synthesis and absolute configuration of acanthodendrilline, a new cytotoxic bromotyrosine alkaloid from the Thai marine sponge Acanthodendrilla sp. Chem Pharm Bull 2016; 64: 258 – 262

[3] Ingkaninan K, Temkitthawon P, Chuenchom K, Yuyaem T, Thongnoi W. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol 2003; 89: 261 – 264

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