title: Synthesis, structural studies, and cytostatic evaluation of 5,6-di-O-modified L-ascorbic acid derivatives.
abstract: The 5,6-di-O-tosylated derivative of l-ascorbic acid was synthesized by selective protection and deprotection of 2,3- and 5,6-dihydroxy functional groups involving 5,6-ditosylation in the final step, while the novel 6-acetoxy, 6-hydroxy, and 6-chloro derivatives of 4,5-didehydro-l-ascorbic acid were obtained by reaction of ditosylated compound with nucleophilic reagents. The analysis of 3JH-4-H-5 homonuclear coupling constants shows that all l-ascorbic acid derivatives except for epoxy and 4,5-didehydro compounds exist in high population as gauche conformers across C-4-C-5 bonds, while 3JC-3-H-5 heteronuclear coupling constants in 4,5-didehydro derivatives indicate cis geometry along C-4-C-5 double bond. The X-ray crystal structure analysis of 2,3-di-O-benzyl-5,6-epoxy- and 5,6-isopropylidene-l-ascorbic acid shows that the oxygen atoms attached at positions 2 and 3 of the lactone ring are disposed in a synperiplanar fashion. Besides that, the dioxolane ring adopts half-chair conformation. The molecules of epoxy derivative are joined into infinite chains by one weak hydrogen bond of C-H...O type. Two O-H...O, and C-H...O hydrogen bonds link the molecules of 5,6-di-O-isopropylidene compound into two-dimensional network. 6-Chloro derivative of 2,3-di-O-benzyl-l-ascorbic acid showed the best cytostatic effects against all tested malignant tumor cells (IC50: approximately 18 microM).
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Gazivoda
authors.forename: Karlo
authors.initials: K
authors.lastname: Wittine
authors.forename: Iva
authors.initials: I
authors.lastname: Lovrić
authors.forename: Damjan
authors.initials: D
authors.lastname: Makuc
authors.forename: Janez
authors.initials: J
authors.lastname: Plavec
authors.forename: Mario
authors.initials: M
authors.lastname: Cetina
authors.forename: Draginja
authors.initials: D
authors.lastname: Mrvos-Sermek
authors.forename: Lidija
authors.initials: L
authors.lastname: Suman
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Kresimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Mladen
authors.initials: M
authors.lastname: Mintas
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D001205:Ascorbic Acid