Iantherans A and B, unique dimeric polybrominated benzofurans as Na,K-ATPase inhibitors from a marine sponge, Ianthella sp.

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Abstract

Two novel tetrabrominated benzofuran derivatives, named iantherans A and B, were isolated from an Australian marine sponge of the genus Ianthella. The unique structures comprised of 2,3-bis(sulfooxy)-1,3-butadiene and two brominated benzofuran moieties were determined by spectroscopic and chemical methods. Iantheran A has a (Z,Z)-1,3-butadiene moiety, whereas iantheran B is the geometric isomer possessing a (Z,E)-1,3-butadiene moiety. The inhibitory activities of the iantherans and their derivatives against Na,K-ATPase as well as the efficacy of iantheran A against other several enzymes were evaluated.

Introduction

The sodium–potassium-activated adenosine triphosphatase (Na,K-ATPase) is a ubiquitous sodium pump that is expressed in the membrane of most eukaryotic cells.1 The pump is the only known receptor for the cardiac glycosides, e.g. Digitalis toxins such as digoxin, used to treat congestive heart failure and cardiac arrhythmias. Even though the cardiac glycosides are widely used in the treatment of such heart diseases, the therapeutic index is low. From the need for relatively safe agents for the successful treatment of the failing heart, researchers have made their efforts to find novel inhibitors of the sodium pump.1, 2 In our search program for Na,K-ATPase inhibitors of marine origin, we recently isolated a quite unique tetrabrominated benzofuran metabolite, iantheran A (1),3 and four novel dibromotyrosine derivatives, ianthesines,4 from an Australian marine sponge of the genus Ianthella as active components. The sponges of the genus Ianthella (order Verongida, family Ianthellidae) and the others belong to the Verongida order and are well known to produce several bromotyrosine-derived metabolites, such as the ianthesines,4 purealin,5 and others,6 whereas 1 is a quite novel type of polybrominated metabolite. A further investigation of an active fraction of the sponge extract resulted in the isolation of a geometric isomer of 1, iantheran B (2), which also showed a similar Na,K-ATPase inhibitory activity. This paper describes the structure elucidation of 2 as well as the full details of the isolation and biological evaluation of 1 and 2 (Fig. 1).

Section snippets

Results and discussion

The EtOAc soluble fraction4 obtained from the sponge was subjected to bioassay-guided fractionation using column chromatography on silica gel (CHCl3–MeOH–H2O system) to give iantheran A (1) (0.12% of wet sponge) and iantheran B (2) (0.01%).

The major component, iantheran A (1), showed the characteristic isotope peaks in the negative FABMS spectrum at m/z 995, 997, 999, 1001, and 1003 (M−Na) in the ratio of ca. 1:4:6:4:1 due to four bromine atoms in the molecule. The molecular formula of 1 was

General methods

Melting points were uncorrected. HPLC was performed on a Shimadzu LC-8A preparative liquid chromatograph. IR spectra were recorded on a JASCO FT/IR-7000S. UV spectra were recorded on a JASCO Ubest-50 UV–vis spectrophotometer. NMR spectra were recorded on a Brucker-ARX400 (400 MHz). NMR chemical shifts were referenced to the solvent peak of δH 3.30 (residual CHD2OD), 2.04 (residual CHD2COCD3), δC 49 for CD3OD or 29.8 ppm for CD3COCD3. Mass spectra were recorded on a JMS DX-705L (FABMS) or an

Acknowledgements

We are grateful to Dr. Jun Kawabata (Hokkaido University) for the valuable discussions on NMR analysis. This work was financially supported by a grant, Research for the Future Program, from the Japan Society for the Promotion of Science (JSPS).

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Present address: Agroscience Research Laboratories, Sankyo Co., Ltd., Yasu-cho, Yasu-gun, Shiga 520-2342, Japan.

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