title: Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity.
abstract: A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-1-yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3-trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s >/= 40 at -78 degrees C) by means of an oxazaborolidine-catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd(0)-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD50 values down to 9 microM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis.
authors.affiliation: Institut für Organische Chemie, Universität zu Köln, Greinstrasse 4, 50939 Köln, Germany.
authors.forename: Juraj
authors.initials: J
authors.lastname: Velcicky
authors.forename: Andreas
authors.initials: A
authors.lastname: Lanver
authors.forename: Johann
authors.initials: J
authors.lastname: Lex
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Schmalz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D003460:Crystallization; D003500:Cyclization; D006801:Humans; D006868:Hydrolysis; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D028561:Transition Elements / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007659:Ketones; D009705:Nucleosides; D028561:Transition Elements