ChemInform Abstract: Fungal Cyclooligomer Depsipeptides: From Classical Biochemistry to Combinatorial Biosynthesis

Suessmuth, Roderich D.; Mueller, Jane; Doehren, Hans von; Molnár, István

doi:10.1002/chin.201118257

Cited by 14 publications

(25 citation statements)

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“…To achieve all three of these goals without compromising synthetic efficiency or relevance to complex natural products, we were attracted to cyclodepsipeptides, in which biological activity is quite diverse (18)(19)(20)(21)(22)(23). Herein, we report rapid access to size-diverse collections of cyclooligodepsipeptides using a controlled oligomerization/macrocyclization sequence.…”

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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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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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“…(−)-Verticilide (nat-1) is a fungal cyclooligomeric depsipeptide (COD) natural product, derived from alternating α-hydroxy acid and α-amino acid monomers. Fungal CODs are structurally privileged natural products as demonstrated by their broad spectrum of biological activities, including antibiotic, insecticidal, and antitumor activities (26). Some CODs bind ions (27,28) and serve as transporters across cell membranes-a feature which may contribute to their bioactivity (26).…”

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confidence: 99%

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Batiste

Blackwell

Kim

et al. 2019

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

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Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (−)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (−)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2−/−). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2−/− mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.

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“…D-Hiv and L-amino acid are essential substrates for the synthesis of 1-5 (Suessmuth et al, 2011). It is apparent that S. cerevisiae can provide these biosynthetic precursors since we have been able to reconstitute the production of 1-5 in this yeast by only expressing the corresponding 13 CODSs.…”

Section: Improvement Of the Production Of Fungal Cods In S Cerevisiamentioning

confidence: 94%

Engineered production of fungal anticancer cyclooligomer depsipeptides in Saccharomyces cerevisiae

et al. 2013

Metabolic Engineering

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Engineered production of fungal anticancer cyclooligomer depsipeptides in Saccharomyces cerevisiae, Metabolic Engineering, http://dx. doi.org/10. 1016/j.ymben.2013.04.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ChemInform Abstract: Fungal Cyclooligomer Depsipeptides: From Classical Biochemistry to Combinatorial Biosynthesis

Abstract: Review: 154 refs.

Cited by 14 publications

References 1 publication

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

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Engineered production of fungal anticancer cyclooligomer depsipeptides in Saccharomyces cerevisiae

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