title: N⁴-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine-new drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate).
abstract: Amino-bisphosphonates (alendronate, pamidronate) were covalently linked in a three step synthesis, with protected and triazolylated derivatives of therapeutically used nucleoside analogs (5-FdU, araC, AZT) by substitution of their triazolyl residue. From the deprotected and chromatographically purified reaction mixtures N⁴-[alkyl-(hydroxyphosphono) phosphonate]-cytidine combining two differently cytotoxic functions were obtained. This new family of bisphosphonates (BPs) contains as novelty an alkyl side chain with a cytotoxic nucleoside. The BPs moiety allows for a high binding to hydroxyapatite which is a prerequisite for bone targeting of the drugs. In vitro binding of 5-FdU-alendronate (5-FdU-ale) to hydroxyapatite showed a sixfold increased binding of these BPs as compared to 5-FdU. Exploratory cytotoxic properties of 5-FdU-ale were tested on a panel of human tumor cell lines resulting in growth inhibition ranging between 5% and 38%. The determination of IC₅₀-concentrations of the conjugate in Lewis lung carcinoma and murine macrophages showed an incubation time dependent growth inhibition with higher sensitivity towards the tumor cells. We assume that the antimetabolite-BPs can be cleaved into different active metabolites that may exert cytotoxic and other therapeutic effects. However, the underlying mechanisms of these promising new antimetabolite-BPs conjugates remain to be evaluated in future experiments.
authors.affiliation: Institute for Organic Chemistry, University of Tuebingen, Tuebingen, Germany. herbert.schott@uni-tuebingen.de
authors.forename: Herbert
authors.initials: H
authors.lastname: Schott
authors.forename: Daniel
authors.initials: D
authors.lastname: Goltz
authors.forename: Timm C
authors.initials: TC
authors.lastname: Schott
authors.forename: Claudia
authors.initials: C
authors.lastname: Jauch
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
mesh_terms: D019386:Alendronate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001086:Arabinofuranosyluracil / Q000737:chemistry; D050071:Bone Density Conservation Agents / Q000737:chemistry*; D001842:Bone and Bones / Q000187:drug effects; D045744:Cell Line, Tumor; D003562:Cytidine / Q000737:chemistry*; D004164:Diphosphonates / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D017886:Durapatite / Q000737:chemistry; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D000077268:Pamidronate; D014529:Uridine / Q000031:analogs & derivatives / Q000737:chemistry; D015215:Zidovudine / Q000737:chemistry
chemical_list: C575868:5-FdU-alendronate; D000964:Antimetabolites, Antineoplastic; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D001086:Arabinofuranosyluracil; D015215:Zidovudine; C001943:5-fluorouridine; D003562:Cytidine; D017886:Durapatite; D000077268:Pamidronate; D005472:Fluorouracil; D014529:Uridine; D019386:Alendronate