(−)-Ternatin, a highly N-methylated cyclic heptapeptide that inhibits fat accumulation: structure and synthesis

Shimokawa, Kenichiro; Mashima, Itsuka; Asai, Akiko; Yamada, Kaoru; Kita, Masakazu; Uemura, Daisuke

doi:10.1016/j.tetlet.2006.04.073

Cited by 32 publications

(15 citation statements)

References 22 publications

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“…Guided by this assay, we isolated the highly N ‐methylated cyclic heptapeptide (−)‐ternatin ( 1 ) 6 We describe herein the details of our ongoing studies, including the preliminary screening of wild mushrooms, the isolation and structure elucidation of 1 , the chemical synthesis of 1 in the solid phase, and the inhibitory effect of 1 and its stereoisomers on fat accumulation by 3T3‐L1 adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Biological Activity, Structural Features, and Synthetic Studies of (−)‐Ternatin, a Potent Fat‐Accumulation Inhibitor of 3T3‐L1 Adipocytes

Shimokawa¹,

Mashima²,

Asai³

et al. 2008

Chemistry An Asian Journal

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A series of studies, including preliminary screening, isolation, structure determination, synthesis, and biological evaluation, of (-)-ternatin (1) are described. A highly N-methylated cyclic heptapeptide isolated from the mushroom Coriolus versicolor, 1 shows an inhibitory effect on fat accumulation by 3T3-L1 murine adipocytes (EC50 = 0.02 microg mL(-1)). Detailed analysis of 1D and 2D NMR spectra, as well as amino acid analysis, suggested four stereoisomers as candidates for 1. For the complete structural elucidation of 1, chemical syntheses were carried out by solid-phase peptide synthesis. By comparing the spectroscopic data for the natural product with the data for the synthetic stereoisomers, the structure of 1 was confirmed to be cyclo[D-allo-Ile1-L-(NMe)Ala2-L-(NMe)Leu3-L-Leu4-L-(NMe)Ala5-D-(NMe)Ala6-(2R,3R)-3-hydroxy-Leu7].

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Section: Introductionmentioning

confidence: 99%

Biological Activity, Structural Features, and Synthetic Studies of (−)‐Ternatin, a Potent Fat‐Accumulation Inhibitor of 3T3‐L1 Adipocytes

Shimokawa¹,

Mashima²,

Asai³

et al. 2008

Chemistry An Asian Journal

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“…Motivated by its potent antiproliferative activity and unknown mechanism of action, we sought to determine which of the 128 possible stereoisomers (based on 7 unassigned stereocenters) corresponds to A3. Based on our hypothesis that A3 is structurally related to the anti-adipogenic cyclic heptapeptide, ternatin, 9 we previously designed and synthesized "ternatin-4", which incorporates the dehydromethyl leucine (dhML) and pipecolic acid residues found in A3, yet lacks the b-hydroxy group attached to N-Me-Leu ( Figure 1). We discovered that ternatin and ternatin-4 inhibit cancer cell proliferation by targeting eEF1A, with ternatin-4 being up to 500-fold more potent than ternatin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumor eEF1A antagonist SR-A3

Wang¹,

Oltion²,

Al-Khdhairawi

et al. 2020

Preprint

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Ternatin and related cyclic peptides inhibit the elongation phase of protein synthesis by targeting the eukaryotic elongation factor-1α (eEF1A), a potential therapeutic vulnerability in cancer and viral infections. The cyclic peptide natural product “A3” appears to be related to ternatin, but its complete structure is unknown and only 4 of its 11 stereocenters have been assigned. Hence, A3 could be any one of 128 possible stereoisomers. Guided by the stereochemistry of ternatin and more potent structural variants, we synthesized two A3 epimers, “SR-A3” and “SS-A3”. We found that synthetic SR-A3 is indistinguishable from naturally derived A3 and potently inhibits cancer cell proliferation. Relative to SS-A3 and previously characterized ternatin variants, SR-A3 exhibits a dramatically enhanced duration of action. This increase in cellular residence time is conferred, stereospecifically, by a single β-hydroxy group attached to N-methyl leucine. SR-A3 thus exemplifies a mechanism for enhancing the pharmacological potency of cyclic peptide natural products via side-chain hydroxylation.

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“…It has long been recognized that nature prefers certain macrocyclic compounds and their complexes for the performance of many fundamental biological functions, for example, in photosynthesis, formation of vitamin B 12 , oxygen storage and transport in living organisms, etc. Cyclization seems to be a common feature of many nonribosomally produced peptides of a constrained structure that ensures a precise functionality important for a proper interaction with the dedicated molecular target in the cell . Cyclopeptides are also advantageous over acyclic peptides as they are suitable for drug delivery because of their resistance to proteolytic degradation, a process in which peptide bonds are broken down partially into smaller peptides, or completely into amino acids, by proteolytic enzymes, present in bacteria and in plants but most abundant in animals .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Aspects, Antimicrobial Activity, and Ion Transport Investigations of Four New [1 + 1] Condensed 12‐Membered Cyclophane Amides

Gürbüz

Agh-Atabay

Karabulut

2016

Journal of Heterocyclic Chem

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Two new diamines (a, b) and their four [1 + 1] condensed macrocyclic peptides (c–f) were synthesized via dilution method affording the expected dilactams in reasonably high‐yield yields. The compounds were characterized by elemental analyses, mass, FT‐IR, 1H, and 13C NMR spectral data. Mass spectra reveal their [1 + 1] cyclic condensation. The macrocycles having two peptide units in the ring would constitute three configurational isomers: cisoid–cisoid, transoid–transoid, and cisoid–transoid. Their 1H and 13C NMR show one signal for each chemically equivalent SCH2 and CONH and could be assigned symmetrical structures lacking any configurational isomerism. The ion transport activity of the compounds (c) and (d) on Na+ and K+ ions were evaluated by CH2Cl2 liquid–liquid membrane method using a U tube system. Slightly higher affinity for potassium than sodium was also observed, which is undoubtedly related to the matching size of the cavity between K+ and cyclic peptides. The antimicrobial and antifungal activities of four macrocyclic amides (c, d, e, and f) were illuminated using disk diffusion method in dimethyl sulfoxide as well as the minimal inhibitory concentration dilution method, against several bacteria and yeast cultures. Comparing all methods, in most cases, the (e) and (f) compound seems to show slightly higher biological activity than the (c) and (d) macrocycles. This may be because of the presence of extra chlorine atoms on the exterior part of the molecules.

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(−)-Ternatin, a highly N-methylated cyclic heptapeptide that inhibits fat accumulation: structure and synthesis

Cited by 32 publications

References 22 publications

Biological Activity, Structural Features, and Synthetic Studies of (−)‐Ternatin, a Potent Fat‐Accumulation Inhibitor of 3T3‐L1 Adipocytes

Biological Activity, Structural Features, and Synthetic Studies of (−)‐Ternatin, a Potent Fat‐Accumulation Inhibitor of 3T3‐L1 Adipocytes

Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumor eEF1A antagonist SR-A3

Synthesis, Structural Aspects, Antimicrobial Activity, and Ion Transport Investigations of Four New [1 + 1] Condensed 12‐Membered Cyclophane Amides

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