title: Modulating the structure of phenylalanine-incorporated ascidiacyclamide through fluorination.
abstract: We designed four fluorinated Phe-incorporated ascidiacyclamide ([Phe]ASC) analogs, (cyclo(-Xxx1-oxazoline2-D-Val3-thiazole4-Ile5-oxazoline6-D-Val7-thiazole8-)), [(4-F)Phe]ASC (Xxx1: 4-fluorophenylalanine), [(3,5-F₂)Phe]ASC (Xxx1: 3,5-difluorophenylalanine), [(3,4,5-F₃)Phe]ASC (Xxx1: 3,4,5-trifluorophenylalanine) and [(F₅)Phe]ASC (Xxx1: pentafluorophenylalanine), to modulate the π-electron density of the aromatic ring of the Phe residue. X-ray diffraction analysis, ¹H NMR and CD spectra all suggested that the interactions between the benzene ring of the Xxx1 residue and the alkyl groups of oxazoline2 contribute to the stability of the folded structure of these analogs. Substituting fluorines for the hydrogens progressively weakened those interactions through reducing the π-electron density, thereby mediating transformation from the folded to square structure. As a result, [(F₅)Phe]ASC preferred the square form more than the other analogs did. Also contributing to the preference for the square form may be the hindrance of the rotation around the Cα-Cβ bond by the two ortho-fluoro substituents of [(F₅)Phe]ASC. These findings demonstrate that the structure of ASC can be modulated by using fluorine as an electron-withdrawing group.
authors.affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka, 569-1094, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Asano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Doi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D007928:Lethal Dose 50; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D010456:Peptides, Cyclic; D010649:Phenylalanine; C075813:ascidiacyclamide
keywords: 1H NMR; CD spectrum; anisotropic effect; ascidiacyclamide; crystal structure; fluorine; inductive electron withdrawal; phenylalanine; ring-current effect