Molecular conformation of ascidiacyclamide, a cytotoxic cyclic peptide from Ascidian: X‐ray analyses of its free form and solvate crystals

Abstract

In order to investigate the conformational variation of ascidiacyclamide, a cytotoxic cyclic peptide from marine tunicate Ascidian, single crystals were prepared from ethanol and aqueous ethanol solutions as its free form (crystal I) and H2O/0.5 C2H5OH solvate (crystal II), respectively, and were determined by the x-ray diffraction method. Crystal I showed a pseudo C2-symmetric saddle-shaped rectangular conformation. Similar conformations were also observed in crystal II, where there were two crystallographically independent C2-symmetric molecules (named Mol-A and -B) per asymmetric unit. Mol-A and -B included H2O and H2O/C2H5OH solvents within their ring structures, respectively. These water and ethanol molecules were located on the crystallographic dyad axes, and were stabilized by the van der Waals contacts (including hydrogen bonds) with the polar-ring N atoms and nonpolar D-Val side-chain atoms. The conformational characteristics of ascidiacyclamide and its fluctuation/variation were discussed based on the present and previously reported x-ray results.

Conformational change of ascidiacyclamide caused by asymmetric modification for an isoleucine residue: Structural analyses of [Gly], [Leu], and [Phe]ascidiacyclamides by X-ray diffraction and NMR spectroscopy

“…These parameters are summarized in Table I (nmr structure will be discussed later). In both crystal structures of [Leu] and [Ile]ASCs, the distance D and angle values, 3 which represent the stress of cyclic backbone, are similar to each other. Therefore, the replacement of Ile for Leu caused no significant change of the structure in the solid phase.…”

“…In the serial structure analyses, it has been shown that ascidiacyclamide is able to fold to two discrete forms at least (squared and figure 8 forms), which are characterized by the difference of the backbone twisting and the intramolecular hydrogen bond. [2][3][4][5] The similar structures have been also observed in the related tunicate peptides, patellamide A-D, and the conformational equilibrium has been postulated between the different conformers, based on nmr spectroscopic, molecular dynamics, and x-ray diffraction studies. 6 -9 It has been also considered that a "proper" pathway of the conformational change exists in the equilibrium [3][4][5] and the cytotoxicities of these tunicate peptides are brought out by their active conformations in the conformational equilibrium.…”

“…[2][3][4][5] The similar structures have been also observed in the related tunicate peptides, patellamide A-D, and the conformational equilibrium has been postulated between the different conformers, based on nmr spectroscopic, molecular dynamics, and x-ray diffraction studies. 6 -9 It has been also considered that a "proper" pathway of the conformational change exists in the equilibrium [3][4][5] and the cytotoxicities of these tunicate peptides are brought out by their active conformations in the conformational equilibrium. 4 In this study, an Ile residue was substituted by glycine ([Gly]ASC), leucine ([Leu]ASC), or phenylalanine ([Phe]ASC) to disturb the original C 2 symmetry in the chemical structure ( Figure 1) to quantitate the relation between bulkiness and/or hydrophobicity of each residue and the toxicity.…”

Cyclic peptide marine metabolites and CuII

“…A substantial increase in flexibility compared to the cyclic pseudo-hexa-and pseudo-heptapeptides might be expected. However, analysis of the solid state and solution structures by X-ray crystallography, 27,73,74,84,85 1 H-NMR spectroscopy, 19,33,72,85 DFT calculations 74 and molecular mechanics/ Monte Carlo/molecular dynamics-based conformational analyses 27,72 indicated that there are four conformers which we summarize here in two types of conformations: the "saddleshaped", sometimes also referred to as square, and the twisted "figure-of-eight" conformation (Fig. 4).…”

Synthesis and Structural Properties of Patellamide A Derivatives and Their Copper(ii) Compounds

“…This restricts the flexibility to three distinct conformations, usually described as type 1, type 2 (saddle), and type 3 (twisted figure-ofeight). [14,37] It appears that, at least for the bis-seco(oxazoline)-type ligands (PatN, PatJ 1 , PatJ 2 , and PatL), this nomenclature is not appropriate because a) the additional flexibility must lead to further stable conformations, and b) the distinction between saddle and figure-of-eight generally depends on the orientation of the structural plot. This emerges from Figure 2, whichs shows the structures of PatJ 1 , patellamide D, and the dicopper(ii) complex of PatJ 1 .…”