Towards the Synthesis of Inosine Building Blocks for the Preparation of Oligonucleotides with Hydrophobic Alkyl Chains Between the Nucleotide Units 英文参考文献.docVIP

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Towards the Synthesis of Inosine Building Blocks for the Preparation of Oligonucleotides with Hydrophobic Alkyl Chains Between the Nucleotide Units 英文参考文献.doc

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Towards the Synthesis of Inosine Building Blocks for the Preparation of Oligonucleotides with Hydrophobic Alkyl Chains Between the Nucleotide Units 英文参考文献

Molecules 2009, 14, 4326-4336; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Towards the Synthesis of Inosine Building Blocks for the Preparation of Oligonucleotides with Hydrophobic Alkyl Chains Between the Nucleotide Units ? Karl K?stler and Helmut Rosemeyer * Organische Materialchemie und Bioorganische Chemie, Institut für Chemie, Fachbereich Biologie/Chemie, Universit?t Osnabrück, Barbarastr. 7, D-49069 Osnabrück, Germany ? Dedicated to Prof. Dr. Frank Seela on the occasion of his 70th birthday. * Author to whom correspondence should be addressed; E-Mail: Helmut.Rosemeyer@uos.de. Received: 18 September 2009; in revised form: 19 October 2009 / Accepted: 23 October 2009 / Published: 26 October 2009 Abstract: The scientific objective of the research reported in this manuscript was the synthesis of novel phosphoramidite building blocks for the preparation of lipophilic oligonucleotides. Reaction of inosine (4) with 4-oxopentyl-4-methylbenzoate (2c) in the presence of triethyl orthoformate and 4M HCl in 1,4-dioxane gave a diastereoisomeric mixture of the ketals 5. Subsequent 4,4’-dimethoxytritylation at the 5’-hydroxyl afforded (R)-6 + (S)-6 which could be separated chromatographically. Detoluoylation gave compounds (R)-7 and (S)-7. Phosphitylation of a diastereoisomeric mixture of 7 led to a mixture of four diastereoisomers of the corresponding 2-cyanoethylphosphoramidites 8. Keywords: lipophilic oligonucleotides; phosphoramidites; nucleoside ketals Introduction The low cell membrane permeability of oligonucleotides is one major drawback of antisense gene therapy. Therefore, as early as the eighties antisense and antigene oligomers were prepared which carried lipophilic groups, mostly at the termini. Other lipophilic modifications comprise derivatization of: (i) the nucleobases, (ii) of the glyconic residues or (iii) of the phos