Abstract
An improvement to our solid phase strategy to generate pharmacologically interesting molecule libraries is proposed here. The synthesis of newo-chlorophenol-functionalised solid supports with very high loading (0.18–0.22 meq/g for control pore glass (CPG) and 0.25–0.50 meq/g for TG) is reported. To test the efficiency of these supports, we prepared nucleotide and oligonucleotide models, and their coupling yields and the purity of the crude detached materials were comparable to previously available results. These supports allow the facile and high-yield preparation of highly pure phosphodiester and phosphoramidate monoester nucleosides, conjugated oligonucleotides, and other yet unexplored classes of phosphodiester and phosphoramidate molecules.
Highlights
Oligonucleotides (ODNs) and nucleotides represent classes of potential therapeutic agents with a broad spectrum of pharmacological activities
We have recently reported a simple solid phase methodology to obtain phosphodiester and phosphoramidate monoester nucleoside analogues and 5- and 3-ODN conjugates in extremely pure form by using standard phosphotriester chemistry (Scheme 1)
Inspired by Pedroso’s procedure previously developed for the solid phase synthesis of cyclic ODNs [36], we prepared a small library of thymidine analogues conjugated at the 5-position with a set of representative
Summary
Oligonucleotides (ODNs) and nucleotides represent classes of potential therapeutic agents with a broad spectrum of pharmacological activities. Current solid phase methods for the synthesis of ODN conjugates include the utilisation of prefabricated labels, previously converted into the corresponding phosphoramidite or H-phosphonate derivatives, and elaborate supports bearing an appropriate linker to incorporate the conjugating residue, generally employed as a postsynthetic modification of the ODNs [30] In both strategies, stringently applied purifications (in the first approach, for the reactive phosphorylated derivatives of the labels; in the second, for the preparation of the linker or in the final step) are typically required to isolate the desired conjugated molecule in a pure form [31,32,33,34]. Aiming to achieve the synthesis of a solid support with a higher load than that currently available and that is compatible with phosphoramidite and phosphotriester chemistry, we devised a straightforward and efficient synthetic protocol to prepare a new support in which the loading of the o-chlorofunctional group is very high (0.20–0.50 meq/g)
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