title: Synthesis and in vitro activities of new anticancer duplex drugs linking 2'-deoxy-5-fluorouridine (5-FdU) with 3'-C-ethynylcytidine (ECyd) via a phosphodiester bonding.
abstract: Two isomeric cytostatic duplex drugs 2'-deoxy-5-fluorouridylyl-(3'-->5')-3'-C-ethynylcytidine [5-FdU(3'-->5')ECyd] and 2'-deoxy-5-fluorouridylyl-(5'-->5')-3'-C-ethynylcytidine [5-FdU(5'-->5')ECyd] were designed and synthesized at gram scale according to the hydrogenphosphonate method in an overall yield of about 40%. The in vitro evaluation of the anticancer effects indicated highly varying sensibilities of the panel of 60 tested tumor cell lines against the duplex drugs. 5-FdU(3'-->5')ECyd had a 50% growth inhibition (IC(50) < or = 10(-8) M) in 44/58 cell lines. However, only 25/53 of those cell lines showed corresponding IC(50) values when the isomeric 5-FdU(5'-->5')ECyd was tested. Total growth inhibition was achieved using micromolar concentrations of the duplex drugs. The 5-FdU residue of the duplex drug can cause very different effects like additive, synergistic, antagonistic as well as sequence-depending activities, which drastically changed efficiency as well as specificity of the anticancer activities of the duplex drugs, in comparison to those of the monomeric drugs.
authors.affiliation: Institute of Organic Chemistry, University Tuebingen, Auf der Morgenstelle 18, D-72076 Tuebingen, Germany. herbert.schott@uni-tuebingen.de
authors.forename: Herbert
authors.initials: H
authors.lastname: Schott
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D010710:Phosphates
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000964:Antimetabolites, Antineoplastic; D003432:Cross-Linking Reagents; D010710:Phosphates; D005467:Floxuridine; D003562:Cytidine