Ascidiacyclamide [cyclo(-Ile1,5 -oxazoline2,6 -d-Val3,7 -thiazole4,8 -)2 ] is a cytotoxic cyclic peptide from ascidian. Through structural analyses using monosubstituted analogues (Xaa1 : Ala, 2-aminobutyric acid, Val, cyclohexylglycine, and phenylglycine), we previously demonstrated the conformational equilibrium between its square and folded forms. As the bulkiness of the Xaa1 residue side chain was reduced, spontaneous folding was promoted, and the cytotoxicity decreased accordingly. In the present study, five disubstituted analogues in which a tert-leucine residue (Tle) was incorporated at the 5-position of the abovementioned monosubstituted analogues were synthesized, after which their structures were analyzed using X-ray diffraction, circular dichroism (CD) spectral measurements, and 1 H NMR-based quantitative analysis. The side chains of the Tle and Ile residues are structural isomers of one another, and the Tle residue bearing the tert-butyl group can be expected to play a role as a building block. In fact, peptides incorporating Tle5 exhibited much less spontaneous folding than their Ile5 counterparts in both crystal and solution. Increases in enthalpy and entropy due to the tert-butyl group during the folding process resulted in increased conformational free energy (ΔG°). The powerful plasticity of the tert-butyl group would stabilize the square form relating with cytotoxicity.

Effect of the powerful plasticity of the tert-butyl side chain on the conformational equilibrium of ascidiacyclamides.

The chapter's subsections are mainly focused on the derivatives of the thiazole and benzothiazole structural cores. Derivatives of thiazoline, thiazolidine, and benzothiazoline are considered as well. The chapter covers theoretical, structural, spectral, chemical and biological aspects of the chemistry of the thiazole scaffold. 

Thiazoles

Ascidiacyclamide [cyclo(-Ile-oxazoline-D-Val-thiazole-)2] is a cytotoxic cyclic peptide from ascidian. We examined the potential of the CH⋯π interaction at the diagonal position of ascidiacyclamide by comparing the interactions of Ile, Val, Abu (2-aminobutyric acid) or Ala with Ile, Chg (cyclohexylglycine) or Phg (phenylglycine). In solution, ascidiacyclamides are in a conformational equilibrium between square and folded forms. The CH⋯π interaction is expected to contribute to stabilization of the square form, which enhances the peptides' cytotoxicity. The distances between the alkyl side chain of Xaa and the π-plane of Phg were estimated from the crystal structures. The conformational free energies (ΔG°) determined through NMR-based quantitation indicated remarkable stabilization of the square form upon incorporation of Phg. These observations were consistent with the circular dichroism (CD) spectral measurements. Chemical shift perturbation studies suggested that stabilization of the square form of Phg-incorporated peptides was due to the CH⋯π interaction with the alkyl side chain of Xaa. Greater enthalpic losses were caused during the folding process of Phg-incorporated peptides than Ile- or Chg-incorporated peptides. It is suggested that these enthalpic losses are relevant to the CH⋯π interaction energies, which must be disrupted during folding. In addition, the CH⋯π interactions in the Phg-incorporated peptides increased cytotoxicity.

Experimental evidence for CH⋯π interaction-mediated stabilization of the square form in phenylglycine-incorporated ascidiacyclamide

Abstract A total synthesis of balgacyclamide A was reported for the first time in 2020, however, after multiple epimerization studies of β‐hydroxy amides dehydrative cyclization to access oxazolines, we proposed a configurational reassignment from the previous synthetic pathway. Balgacyclamide A is a macrocyclic hexapeptide with antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei rhodesiense . Chemically, its core contains six amino acids that undergo heterocyclization to form one thiazole and two oxazoline rings. Two of the six amino acids are L ‐threonines that play an important role in their synthetic pathway to achieve oxazolines with the right configuration upon epimerization at the β‐carbon. Thus, we investigated the effect of L ‐threonine and L ‐ allo threonine β‐carbon epimerization via the Burgess reagent, diethylaminosulfur trifluoride (DAST), and (NH 4 ) 6 Mo 7 O 24 • 4H 2 O catalyst to support previous oxazoline synthetic studies. Furthermore, the first total synthesis of balgacyclamide A and an epimer is reported via multiple synthetic key steps that involve a tandem sulfur incorporation, cyclization, and aromatization of the thiazole, and a late‐stage β‐hydroxy amide Walden inversion to access both oxazolines. 

Balgacyclamide A: Structural Revision of the First Reported Total Synthesis and Evaluation of Oxazoline Synthesis via β‐Hydroxy Amides Dehydrative Cyclization Conditions

The Phe-incorporated cyclic peptide [cyclo(-Phe1-oxazoline2-d-Val3-thiazole4-Ile5-oxazoline6-d-Val7-thiazole8-)] is in a conformational equilibrium between square and folded forms in solution. In the folded form, a CH⋯π interaction between the Phe1 aromatic ring and the Oxz2 methyl group is observed. We endeavored to control the local conformation and thus modulate the CH⋯π interaction and flexibility of the Phe1 side chain by controlling the electronic substituent effects at the 4-position of the aromatic ring of the Phe1 residue. The effect of the 4-substituent on the global conformation was indicated by the linear relationship between the conformational free energies (ΔGo) determined through NMR-based quantification and the Hammett constants (σ). Electron-donating substituents, which had relatively strong CH⋯π interactions, promoted peptide folding by restraining the loss in entropy. Local control by the 4-substituent effects suggested that the Phe side chain exerts an entropic influence on the folding of these cyclic peptides.

Electronic substituent effect on the conformation of a phenylalanine-incorporated cyclic peptide

Ascidiacyclamide [cyclo(-Ile1,5-oxazoline2,6-D-Val3,7-thiazole4,8-)] (1) is a cytotoxic cyclic peptide from the ascidian, or sea squirt. Through structural analyses using asymmetric analogues [Xxx1: Ala (2), Val (3), Leu (4), Phe (5), cyclohexylalanine (6) and phenylglycine (7)], we previously showed 1 to exist in a conformational equilibrium between square and folded forms. In the present study, five new asymmetric analogues [Xxx1: 2-aminobutyric acid (8), 2-aminopentyric acid (9), tert-butylalanine (10), cyclohexylglycine (11) and tert-leucine (12)] were synthesized, and their structures were analyzed with X-ray diffraction and CD spectral measurements. Variable temperature 1H NMR measurements were performed to determine their equilibrium constants and their thermodynamic parameters. The use of two reference peptides made these quantitative studies possible. T3ASC, which contains three thiazole rings as a result of replacing oxazoline2 with thiazole, and dASC, in which the two oxazoline rings were deleted, were respectively used as square and folded reference peptides. The estimated parameters enabled more detailed discussion of the relationship between the bulkiness of substituents and the conformational free energies (ΔG°) of the peptides as well as the relationship between structure and cytotoxicity. The ΔG° values for peptides 1, 2, 3, 8, 9 and 11 decreased with decreases in the bulkiness of their substituents. We suggest that spontaneous folding is promoted as the bulkiness of substituents decreases. Peptides 7 and 12, which have large positive ΔG° values independently of temperature, did not exhibit spontaneous folding at any temperature; that is, their conformations were very stable in the square form. Peptides 4, 5, 6 and 10 had negative ΔG° values, despite their bulky substituents. Peptides with a positive ΔG° value showed cytotoxicity, and peptides with a negative ΔG° value showed reduced or no cytotoxicity. However, peptides 5 and 6 showed cytotoxicity equal to or stronger than 1. Those ten peptides except for 5 and 6 showed a clear structure–cytotoxicity relationship based on ΔG° values.

/pdf/nmr-based-quantitative-studies-of-the-conformational-1v6gutwcmu.pdf

NMR-based quantitative studies of the conformational equilibrium between their square and folded forms of ascidiacyclamide and its analogues

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Ryoya Ito

Author Tools

Chat about Author

Papers

NMR-based quantitative studies of the conformational equilibrium between their square and folded forms of ascidiacyclamide and its analogues