Effect of asymmetric modification on the conformation of ascidiacyclamide analogs.
Ascidiacyclamide (ASC), cyclo(-Ile1-Oxz2-d-Val3-Thz4-)2 (Oxz=oxazoline and Thz=thiazole) has a C2-symmetric sequence, and the relationships between its conformation and symmetry have been studied. In a previous study, we performed asymmetric modifications in which an Ile residue was replaced by Gly, Leu or Phe to disturb the symmetry [Doi et al. (1999) Biopolymers49, 459-469]. In this study, the modifications were extended. The Ile1 residue was replaced by Gly, Ala, aminoisobutyric acid (Aib), Val, Leu, Phe or d-Ile, and the d-Val3 residue was replaced by Val. The structures of these analogs were analyzed by X-ray diffraction, 1H NMR and CD techniques. X-Ray diffraction analyses revealed that the [Ala1], [Aib1] and [Phe1]ASC analogs are folded, whereas [Val1]ASC has a square form. These structures are the first examples of folded structures for ASC analogs in the crystal state and are similar to the previously reported structures of [Gly1] and [Phe1]ASC in solution. The resonances of amide NH and Thz CH protons linearly shift with temperature changes; in particular, those of [Aib1], [d-Ile1] and [Val3]ASCs exhibited a large temperature dependence. DMSO titration caused nonlinear shifts of proton resonances for all analogs and largely affected [d-Ile1] and [Val3]ASCs. A similar tendency was observed upon the addition of acetone to peptide solutions. Regarding peptide concentration changes, amide NH and Thz CH protons of [Gly1]ASC showed a relatively large dependence. CD spectra of these analogs indicated approximately two patterns in MeCN solution, which were related to the crystal structures. However, all spectra showed a similar positive Cotton effect in TFE solution, except that of [Val3]ASC. In the cytotoxicity test using P388 cells, [Val1]ASC exhibited the strongest activity, whereas the epimers of ASC ([d-Ile1] and [Val3]ASCs), showed fairly moderate activities.
Asano
A
A
Osaka University of Pharmaceutical Sciences, Osaka, Japan.
Minoura
K
K
Yamada
T
T
Numata
A
A
Ishida
T
T
Katsuya
Y
Y
Mezaki
Y
Y
Sasaki
M
M
Taniguchi
T
T
Nakai
M
M
Hasegawa
H
H
Terashima
A
A
Doi
M
M
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D007941:Leukemia P388; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D012997:Solvents; D013696:Temperature; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D012997:Solvents; C075813:ascidiacyclamide; D004121:Dimethyl Sulfoxide