Functional Analysis of Synthetic Substructures of Polytheonamide B: A Transmembrane Channel‐Forming Peptide

Matsuoka, Shigeru; Shinohara, Naoki; Takahashi, T; Iida, M.; Inoue, M.

doi:10.1002/anie.201101533

Cited by 19 publications

(9 citation statements)

References 49 publications

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“…479 The potent cytotoxicity of polytheonamide B (68 pM vs. P388) is due to the ability to form active H + channels through cell membranes. 480 The absolute conguration of pinnarine 607 (Halichondria okadai, Mie Prefecture, Japan), was determined by synthesis from authentic pinnaic acid. 481 Insight regarding the pharmacophore of the microtubule stabilisers peloruside C 608 and D 609 (Mycale hentscheli, Pelorus Sound, New Zealand) has been aided by semi-synthesis of analogues from peloruside A.…”

Section: Spongesmentioning

confidence: 99%

Marine natural products

et al. 2013

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This review covers the literature published in 2011 for marine natural products, with 870 citations (558 for the period January to December 2011) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1152 for 2011), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

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Section: Spongesmentioning

confidence: 99%

Marine natural products

et al. 2013

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“…Solution structure (Hamada et al, 2010) and synthesis (Inoue et al, 2010) of this unique NRP were achieved five years later. This highly cytotoxic compound is a transmembrane channel-forming peptide (Matsuoka et al, 2011). 13.2 Ribosomal-and Nonribosomal-Derived Peptides: A Virtually Unlimited Source of New Active Compounds j 289…”

Section: Ribosomal-and Nonribosomal-derived Peptides: a Virtually Unlmentioning

confidence: 99%

Marine Peptide Secondary Metabolites

Banaigs

Bonnard

Witczak

et al. 2014

Outstanding Marine Molecules

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A large pro port ion of the marine natural produc ts actu ally u n der clinical inve stigat ion are pept ide sec ondary metabolites with unusual amino acids re sidues. This growing f amily of compounds can be produced via tw o major p athw ays, r ibosomal and nonribosomal. In this c hapt er a re p re sent ed a nd illu strated, with a fe w f amou s examples, ribosomal-and n onribosomal-d erived pe ptides. Atte ntion is focused on fi ve families of biological ly a ctive marine p eptides of d iverse origin, ranging from the old est living ce ll of the world, the cyanobact eria, to more sophisticat ed organisms s uch a s tu nicates or mol lusk s. T he discu ssed pe ptides illu strate d iff erently th e s tructural fe atu re s and diversity f ound in mari ne-derived peptid es; laxaphycins as an example o f true pept ide s; dolast atins, didemnins and kahalalides are discuss ed in connectio n wit h their cl inical trials; a nd azole/azoli ne-c ontaining cyanobactins to exe m plif y the extra ord ina ry c hemi cal dive rs it y wit hin a single organism. Information abou t their biol ogical properties and mec hanisms of a ctio n is disc uss ed when available .

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“…[7] Althought his exceedingly complex structurew as chemically as-sembled, the long overall route (161 total steps) impeded systematicb iological applications of 1. [8] Accordingly,w en ext devised as ynthetically more accessible analogue of 1 as ap arent structure for detailed studies on the structure-activity relationship (SAR). Six amino acid residues of 1 werer eplaced to designasimplified d,l-alternating 48-mer peptide, namely, dansylated polytheonamide mimic 2 (5213Da, Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Dual Chemical Modification of a Polytheonamide Mimic: Rational Design and Synthesis of Ion‐Channel‐Forming 48‐mer Peptides with Potent Cytotoxicity

Hayata

Itoh

Matsutaka

et al. 2016

Chemistry A European J

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Polytheonamide B (1) is a natural peptide that displays potent cytotoxicity against P388 mouse leukemia cells (IC =0.098 nm). Linear 48-mer 1 is known to form monovalent cation channels on binding to lipid bilayers. We previously developed a fully synthetic route to 1, and then achieved the design and synthesis of a structurally simplified analogue of 1, namely, dansylated polytheonamide mimic 2. Although the synthetically more accessible 2 was found to emulate the channel function of 1, its cytotoxicity was decreased 120-fold. Herein, the chemical preparation and biological evaluation of seven analogues 3-9 of 2 are reported. Compounds 3-9 were modified at their N terminus and/or the side chain of residue 44 of 2 to alter their physicochemical properties. The total synthesis of 3-9 was accomplished in a unified fashion by a combination of solid-phase and solution-phase chemistry. Systematic evaluation of the hydrophobicities, single-channel currents, ion-exchange activities, and cytotoxicities of 3-9 revealed that their hydrophobicities are correlated with the total magnitude of ion exchange and determine their cytotoxic potency. Consequently, the most hydrophobic analogue 9 exhibited the lowest IC value, which is comparable to that of 1. Therefore, these results clarified that the bioactivity of the polytheonamide-based peptides can be rationally controlled by changing their hydrophobicity at the N and C termini of the 48-amino-acid sequence.

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Functional Analysis of Synthetic Substructures of Polytheonamide B: A Transmembrane Channel‐Forming Peptide

Cited by 19 publications

References 49 publications

Marine natural products

Marine natural products

Marine Peptide Secondary Metabolites

Dual Chemical Modification of a Polytheonamide Mimic: Rational Design and Synthesis of Ion‐Channel‐Forming 48‐mer Peptides with Potent Cytotoxicity

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