N super(4)-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine - New drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate)

• Published in: Bioorganic & medicinal chemistry 2011-06, Vol.19 (11), p.3520-3526
• Main Authors: Schott, Herbert, Goltz, Daniel, Schott, Timm C, Jauch, Claudia, Schwendener, Reto A
• Format: Article
• Language: English
• Subjects: Alendronic acid; Antimetabolites; Bisphosphonates; Bone; Cytotoxicity; Drug delivery; Drugs; Hydroxyapatite; Lung carcinoma; Macrophages; Metabolites; New families; Novelty; nucleoside analogs; Pamidronic acid; Tumor cell lines; Zidovudine
• ISSN: 0968-0896
• DOI: 10.1016/j.bmc.2011.04.015

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 N super(4)-[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 IC sub(50)-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. New cytostatic antimetabolite-bisphosphonates.