Effects of amino acids and chirality for molecular folding of desoxazoline-ascidiacyclamide derivatives: X-ray crystal structures of four cyclic octapeptides including unusual amino acids,cyclo(-Ile-aThr-D-Val-Thz-)2,cyclo(-Ala-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-),cyclo(-Val-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-), andcyclo(-Ile-aThr-Val-Thz-Ile-aThr-D-Val-Thz-)

Abstract

Desoxazoline derivative of ascidiacyclamide (1), cyclo(–L‐Ile–L‐allo‐threonine–D‐Val–thiazole–)2, was modified to disturb the C2‐symmetry. An Ile1 residue of 1 was replaced for Ala (2) or Val (3), and the D‐Val3 residue was replaced for Val (4). The crystal structures of 1–4 were analyzed by x‐ray diffraction methods. The molecules of all compounds were folded and this type of structure was not observed in x‐ray structures of ascidiacyclamide derivatives so far except for patellamide D. The folding patterns of 1–4 were similar to each other and resembled that of patellamide. The asymmetric modifications at position 1 caused the conformational changes at local area, and these were related with the peptide–peptide and peptide–solvent interactions. Despite the diverse backbone conformation by the epimeric modification at position 3, the entire molecule of 4 was folded. These results mean that (1) the desoxazoline‐ascidiacyclamides favored the folded structures and (2) the modifications of the side chain size at position 1 and the chirality at position 3 brought the local conformational changes to derivatives, suggesting that (3) the lack of the oxazoline block leads to conformational flexibility of 1–4, which accepts the conformational change with no drastic change on the entire structure. © 2001 John Wiley & Sons, Inc. Biopolymers 58: 295–304, 2001

Conformational restraints induced by modification of configuration of threonine and oxazoline residues in ascidiacyclamide analogues

“…2a). This position was previously observed in d ASC analogues having S configurations at the α ‐position of second and sixth residues (10). By contrast, 5 contains D‐ allo ‐Thr (D‐ a Thr) residues having R configuration at the α ‐position, and their side chain positions are equatorial (Fig.…”

“…The MOE calculations (CCG, Quebec, Canada) indicate that the structure of 5 has 32.9 kcal/mol higher potential energy than that of 3 . Nevertheless, the structures of both 3 and 5 are similar to those of the known folded forms of ASC (4,8) and d ASC analogues (10,11).…”

“…These modifications showed that the Oxz residues were the pivot around which molecular folding occurred in all folded forms. Furthermore, desoxazoline‐ascidiacyclamide analogues ( d ASC), which were designed with the expectation of reducing conformational restraints imposed by the five‐membered Oxz rings, all assumed the folded form (10,11). Indeed, even when only one of the two Oxz residues was substituted the molecule assumed the folded form (12).…”

Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity

“…It is likely the Oxz and Thz units limit rotation of the N―C αbonds (the ϕangle of natural peptides). Consistent with that idea, desoxazoline ASC analogues, which lack Oxz rings, are less conformationally restricted than other analogues and are all in the folded conformation . In an earlier report, Shioiri et al also pointed out the importance of the Oxz unit for the cytotoxic activity of cyclic peptides of marine origin .…”

Conformational transformation of ascidiacyclamide analogues induced by incorporating enantiomers of phenylalanine, 1-naphthylalanine or 2-naphthylalanine

“…In the Figure , the high‐field shifts because of ring‐current effects between αH, βH, and γH of Oxz 2 and the aromatic ring of Xxx 1 , except d ‐1Nal 1 , are shown relative to the corresponding signals in [ l ‐Ala]ASC. [ l ‐Ala]ASC, in which a l ‐Ala residue was incorporated at the Xxx 1 position, favored the folded structure in solution . The Δδ value in Figure shows the difference between the chemical shifts of [Xxx]ASC and [ l ‐Ala]ASC (Δδ = δ [Xxx]ASC − δ [Ala]ASC ).…”