Zooxanthellamide Cs:  Vasoconstrictive Polyhydroxylated Macrolides with the Largest Lactone Ring Size from a Marine Dinoflagellate of <i>Symbiodinium </i>sp.

Onodera, Kazunari; Nakamura, Hideshi; Oba, Yuichi; Ohizumi, Yasushi; Ojika, Makoto

doi:10.1021/ja050810g

Cited by 39 publications

(29 citation statements)

References 18 publications

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“…Future studies will explore this tool further, perhaps enabling higher levels of selectivity favoring large macrocycles. In this vein, the existence of large macrocyclic natural products is notable (61,62) as is the dearth of methods that provide rapid access to this size regime.…”

Section: Resultsmentioning

confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.Mitsunobu | total synthesis | collective | macrocycle | oligomerization I nterest in the preparation and use of small molecules exhibiting macrocyclic rings is growing at a tremendous pace, driving the development of new approaches, new chemical reactions, and the underlying chemistry and tools (catalysts) to support them. Historically, studies of macrocyclization reactions have been guided by natural products bearing unusually large carbocycles or mediumand large-ring lactones, amides, and ethers. Fragmentation reactions of polycyclic molecules have long played a role in access to medium-sized macrocycles, whereas macrocyclizations to lactones and amides are often accomplished from linear precursors at high dilution. Insofar as these efforts were typically driven by the goal to prepare a specific macrocycle, often in the form relevant to a natural product synthesis or an engineered constraint to a peptide, absent from the field is an approach that provides rapid access to collections (1) of natural product-like macrocycles, particularly from stereochemically complex, functionally rich, linear precursors (2-6).Pioneers in this area have recorded some success (Fig. 1). Esterification reactions of activated hydroxy acids have led predominantly to diolides, (7-10) and in a single case, oligolides (11). Amidation reactions of activated polypeptides were central to the preparations of macrocyclic peptides by Rothe and Kreiss (12,13) and Wipf and coworkers (14, 15), but they were low yielding and size nonselective. Burke and coworkers (16,17) have shown that the efficiency of an 18-membered oligol...

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Section: Resultsmentioning

confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It is important to note that zooxanthellae of the genus Symdiodinium, which live in symbiosis with the hydrocorals, produce large polyhydroxylated secondary metabolites, namely, zooxanthellatoxins Nakamura et al, 1993) and zooxanthellamides (Onodera et al, 2004;Onodera et al, 2005;Fukatsu et al, 2007) that are of interest due to their characteristic structure and potent vasoconstrictor activity. Recently, we found indirect evidence that the hydrocorals, not the symbiotic zooxanthellae, are the source of the vasoactive compounds present in the M. complanata aqueous extract, since we demonstrated that the extract prepared from bleached specimens displayed concentration-dependent vasoconstrictor effects that were not significantly different from those induced by the extract obtained from the control specimens .…”

Section: Discussionmentioning

confidence: 99%

Systemic toxic effects induced by the aqueous extract of the fire coral Millepora complanata and partial purification of thermostable neurotoxins with lethal effects in mice

García-Arredondo

Rojas‐Molina

Bah

et al. 2015

Comparative Biochemistry and Physiology Part C: Toxicology &

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“…[2][3][4][5] In previous studies, we examined a different strain (HA3-5) of Symbiodinium and discovered another class of large polyols, zooxanthellamides (ZADs), which are distinguishable from the zooxanthellatoxins by three substructures connected via amide functionalities. [6][7][8] Zooxanthellamide C's (ZAD-C's), an isomeric mixture, contain the components with the largest lactone ring size as natural products and have higher vasoconstrictive activity than the zooxanthellatoxins. 8 A further search for the Symbiodinium metabolites using the strain JCUCS-1 resulted in the isolation of the third type of polyols named zooxanthellamide D (ZAD-D, 1), which consists of two substructures connected via an amide group.…”

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confidence: 99%

“…[6][7][8] Zooxanthellamide C's (ZAD-C's), an isomeric mixture, contain the components with the largest lactone ring size as natural products and have higher vasoconstrictive activity than the zooxanthellatoxins. 8 A further search for the Symbiodinium metabolites using the strain JCUCS-1 resulted in the isolation of the third type of polyols named zooxanthellamide D (ZAD-D, 1), which consists of two substructures connected via an amide group. We report herein the isolation, structure elucidation, and biological activity of this new metabolite.…”

mentioning

confidence: 99%

Zooxanthellamide D, a Polyhydroxy Polyene Amide from a Marine Dinoflagellate, and Chemotaxonomic Perspective of the Symbiodinium Polyols

et al. 2007

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A long-chain polyhydroxy polyene amide, zooxanthellamide D (ZAD-D, 1, C54H83NO19), was isolated from a cultured marine dinoflagellate of the genus Symbiodinium. ZAD-D (1) is a polyhydroxy amide consisting of a C22-acid part and a C32-amine part and furnishes three tetrahydropyran rings and six isolated butadiene chromophores. The relative stereochemistry of the tetrahydropyran ring systems was elucidated by NMR techniques. This metabolite showed moderate cytotoxicity against two human tumor cell lines. A phylogenetic tree of Symbiodinium has been updated and compared with the structures of the hitherto isolated polyols of Symbiodinium, zooxanthellatoxins and zooxanthellamides, providing a promising chemotaxonomic perspective for the classification of this morphologically indistinguishable dinoflagellate.

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Zooxanthellamide Cs: Vasoconstrictive Polyhydroxylated Macrolides with the Largest Lactone Ring Size from a Marine Dinoflagellate of Symbiodinium sp.

Cited by 39 publications

References 18 publications

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Systemic toxic effects induced by the aqueous extract of the fire coral Millepora complanata and partial purification of thermostable neurotoxins with lethal effects in mice

Zooxanthellamide D, a Polyhydroxy Polyene Amide from a Marine Dinoflagellate, and Chemotaxonomic Perspective of the Symbiodinium Polyols

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