title: 3-Fluoroazetidinecarboxylic Acids and trans,trans-3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar.
abstract: Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze. This paper describes the synthesis of 3-fluoro-Aze amino acids as hydroxy-Aze analogues which are not susceptible to aldol cleavage. 4-(Azidomethyl)-3-fluoro-Aze and 3,4-difluoroproline are new peptide building blocks. trans,trans-2,4-Dihydroxy-3-fluoroazetidine, an iminosugar, inhibits the growth of pancreatic cancer cells to a similar degree as gemcitabine.
authors: †Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
authors: Zilei
authors: Z
authors: Liu
authors: †Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
authors: Sarah F
authors: SF
authors: Jenkinson
authors: †Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
authors: Tom
authors: T
authors: Vermaas
authors: ‡Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Isao
authors: I
authors: Adachi
authors: §Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, U.K.
authors: Mark R
authors: MR
authors: Wormald
authors: ∥Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan.
authors: Yukako
authors: Y
authors: Hata
authors: ∥Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan.
authors: Yukiko
authors: Y
authors: Kurashima
authors: ∥Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan.
authors: Akira
authors: A
authors: Kaji
authors: ⊥CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P.R. China.|#National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P.R. China.
authors: Chu-Yi
authors: CY
authors: Yu
authors: ‡Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Atsushi
authors: A
authors: Kato
authors: †Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.|#National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P.R. China.
authors: George W J
authors: GW
authors: Fleet
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000599410:2,4-dihydroxy-3-fluoroazetidine; D000970:Antineoplastic Agents; D001384:Azetidines; D050111:Imino Sugars; D010455:Peptides; D011392:Proline