Published papers

New 13-epi-neoverrucosane-type diterpenes 1 and 2 were isolated from the marine sponge Axinyssa tethyoides. Their structures were elucidated by 2D-NMR spectroscopy, the modified Mosher's method, and fluorescent X-ray analysis. 1 and 2 are the first 13-epi-neoverrucosane-type diterpenes that possess a sulfate group.

The diene-yne-diene precursor of the ABC-ring fragment of norzoanthamine, a bioactive alkaloid from the colonial zoanthid Zoanthus sp., was prepared.

Five new polyketides, biselides A (1), B (2), C (3), D (4), and E (5), were isolated from the Okinawan ascidian Didemnidae sp. Their structures were determined by spectroscopic analysis. Biselides A (1), B (2), and C (3) showed cytotoxicity against human cancer cells NCI-H460 and MDA-MB-231.

Novel 2-alkylpyridine alkaloids, phormidinines A (1) and B (2), were isolated from cyanobacterium Phormidium sp. Their structures were determined by spectroscopic analysis. The absolute stereochemistry of 1 was established by the modified Mosher's method.

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

A novel cysteine derivative, spongiacysteine (1), was isolated from marine sponge Spongia sp. The gross structure was elucidated by detailed spectroscopic analysis, and the absolute stereostructure was established by its total synthesis. This compound showed moderate antimicrobial activity against rice blast fungus Pyricularia oryzae.

The bioassay-guided fractionation of the cytotoxic constituents of the Japanese sea hare Dollabella auricularia led to the isolation of aurilide (1), a 26-membered cyclodepsipeptide. The gross structure of 1 was established by spectroscopic analysis including 2D NMR techniques. The absolute stereostructure was determined by chiral HPLC analysis of acid hydrolysates of 1 and by the enantioselective synthesis of a degradation product arising from a dihydroxylated fatty acid portion. The enantioselective synthesis of 1 was achieved in 12% overall yield (16 steps) and confirmed the absolute stereostructure of 1. The cytotoxicity of 1 was evaluated using a synthetic sample, which was found to exhibit potent cytotoxicity against HeLa S 3 cells with an IC50 of 0.011 μg/mL. Further biological and pharmacological studies of 1 have been carried out by using synthetic 1. Graphical abstract.

Two new macrolides, biselides A (1) and B (2), were isolated from the Okinawan ascidian Didemnidae sp. Their structures were determined by spectroscopic analysis.

The first total synthesis of the enantiomer of jolkinolide D, a bioactive diterpene from Euphorbia jolkini Boiss, was achieved from abietic acid. The enantiomer did not exhibit the biological activities that the natural jolkinolide D possesses.

Mycalolide analog 4, consisting only of the side chain of mycalolide B (2), was stereoselectively synthesized and was found to have strong actin-depolymerizing activity.

This account describes bioorganic studies on marine natural products with bioactivity, such as antitumor activity and feeding attractance. Chemical studies on the following bioactive compounds of marine origin have been carried out: 1) feeding attractants for the starfish Acanthaster planci, 2) potent toxins from shellfish of the genus Pinna that cause food poisoning, and 3) a variety of cytotoxic and antitumor compounds from marine invertebrates including sea hares, Dolabella auricularia and Aplysia kurodai. Their isolation, structure elucidation, synthesis, and some aspects of their biological activities are summarized.

Tribromoacetamide was isolated from the Okinawan alga Wrangelia species, and the biological activities of this compound and its analogs were investigated.

A novel cytotoxic compound, nakiterpiosin (1), was isolated from the Okinawan sponge Terpios hoshinota. Its structure was determined by spectroscopic analysis. The absolute stereostructure of 1 was also determined by a modified Mosher's method. Nakiterpiosin showed potent cytotoxicity against P388 cells.

Two unique cytotoxic diterpene alkaloids, haterumaimides J and K, were isolated from the ascidian Lissoclinum sp. Their structures were elucidated by an extensive analysis of spectral data. Haterumaimides J and K showed potent cytotoxicity against P388 cells, with IC50 values of 0.23 ng/mL and 0.45 ng/mL, respectively.

Hedathiosulfonic acids A and B were isolated from the deep-sea urchin Echinocardium cordatum and were determined to be novel 6-undecanethiosulfonic acids by 2D NMR, HRMS, and methylation reaction. The stereostructure of hedathiosulfonic acid A was determined by the analysis of its degradation product, a cyclic β-hydroxysulfone. Hedathiosulfonic acids exhibited acute toxicity. We carried out various model reactions of the olefinic compounds with thiosulfonic acids and proved that, as is the case with natural products, synthesized thiosulfonic acid possessing a carbon-carbon double bond was converted into β-hydroxysulfone in the presence of oxygen.

The enantioselective synthesis of attenols A and B, cyclic polyethers of marine origin, was accomplished on a semigram scale by using diastereoselective hydroboration, coupling with lithium acetylide, Lindlar reduction and acid-catalyzed acetal formation. The configuration of the remaining undetermined spiro acetal carbon was unambiguously determined to be 11S using this ample supply of attenol A. The antitumor activities of synthetic attenol A were also examined.

Artificial analogs of aplyronine A (1), a potent antitumor macrolide, were synthesized and structure-activity (cytotoxicity and actin-depolymerizing activity) relationships were investigated; the side-chain in 1 was found to play a key role in both biological activities.

Terpiodiene (1), a novel tricyclic alcohol, was isolated from the Okinawan sponge Terpios hoshinota, which overgrows and kills corals. Its structure was determined by spectroscopic analysis and the modified Mosher's method. This compound exhibited moderate cytotoxicity against P388 cells.

In the tropical zones of the Indo-Pacific Oceans, the crown-of-thorns sea star Acanthaster planci, as the predator of corals, destroys coral reefs. We recently found that viscera of the sea urchin Toxopneustes pileolus produced a feeding attractant for this sea star. Using our simple bioassay system, we isolated arachidonic acid and α-linolenic acid as feeding attractants from T. pileolus. This is the first report about the sea star A. planci being attracted to unsaturated fatty acids. Interestingly, other unsaturated fatty acids such as eicosapentaenoic acid, docosahexaenoic acid and linoleic acid showed no activity. Our preliminary experiments indicated that these attractants have an attractive effect for the sea star both in the aquarium and in the sea. We anticipated that these attractants could be used to control A. planci. In addition, we verified the existence of arachidonic acid in the coral as one of the feeding attractants.