Solid Phase Synthesis of a Metronidazole Oligonucleotide Conjugate 英文参考文献.docVIP

Molecules 2006, 11, 486-495 molecules ISSN 1420-3049 Full Paper Solid Phase Synthesis of a Metronidazole Oligonucleotide Conjugate Andrew J. Walsh, Michael L. Davis and William Fraser * School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK Tel.: +44 121 204 3940, Fax. +44 121 359 0733 * Author to whom correspondence should be addressed; E-mail: w.fraser@aston.ac.uk Received: 26 April 2006; in revised form: 23 May 2006 / Accepted: 29 May 2006 / Published: 23 June 2006 Abstract: Direct, solid phase synthesis of an oligonucleotide conjugate of the antibiotic drug metronidazole was accomplished by the phosphoramidite method. Removal of protecting groups and cleavage from the controlled pore glass (CPG) solid support was successful using mild conditions (20% Et 3N in pyridine, then conc. NH 3 (aq) at rt for 30 min) whereas standard conditions (conc. NH3 (aq) at 55 °C for 16 h) cleaved the drug. Keywords: CPG, conjugate, metronidazole, oligonucleotide, phosphoramidite, solid phase. Introduction Nitroimidazoles, notably metronidazole (1), are important for the treatment of a wide range of anaerobic bacterial and protozoan infections due their ability to damage and cleave microbial DNA, selectively, under oxygen deficient conditions [1-4]. Although resistance to this class of drug is still low, there are reports of its increase [5-9], therefore improvements to delivery, targeting, localization and mode of action of such nitroimidazoles, would be beneficial [10]. With their ability to position within oxygen-deficient tissue, nitroimidazole derivatives have been investigated as chemotherapeutic agents and radiosensitizers in the treatment of hypoxic tumours [2,11,12]. Although studies suggest that metronidazole and its metabolites cause damage to DNA and mutagenicity in normal human cells, the data remain contradictory [13,14]. Solution chemistry has allowed attachment of the