Efficient microwave-assisted solid phase coupling of nucleosides, small library generation, and mild conditions for release of nucleoside derivatives

Abstract

Nucleosides are essential bio-molecules that participate in a wide array of biological processes involved in maintaining physiologic homeostasis. Recent efforts geared towards the synthesis of nucleoside analogues and development of nucleoside combinatorial libraries using solid phase synthesis has contributed invaluable information towards drug design and development. These studies have provided information concerning the structural requirements of substrate binding pockets of enzymes and evaluation of enzyme kinetics. However, the synthesis of nucleosides and its corresponding analogues remains a challenging and time consuming process. Herein, we report an efficient, microwave assisted solid phase coupling of nucleosides, combinatorial chemistry on the coupled nucleosides to generate small library and mild cleavage conditions to release nucleoside derivatives from its solid support. We anticipate these findings will accelerate the development of synthetic methods or combinatorial library design of nucleoside analogues in similar settings.

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

“…Thus compounds that target the metal site and/or nucleotide-binding site may represent promising approaches toward rational inhibitor design. This approach is actively being explored, as well as inhibitors that target the Trx-APS reductase interface and will be reported in due course [262]. …”

Design, Synthesis and Evaluation of Fe-S Targeted Adenosine 5′-Phosphosulfate Reductase Inhibitors

“…Our synthetic strategy employed polystyrene beads coupled to the ribose 2′ and 3′-hydroxyls via a p -hydroxybenzaldehyde acetal linkage, which provided for minimal protecting group manipulation and can be cleaved from the support using mild acidic conditions [32]. A solid-supported adenosine scaffold allows for selective manipulation of N 6 exocyclic amine and 5′-hydroxyl groups, and facilitates analogue purification.…”

“…Using N -alkylation reaction conditions previously optimized by our group [32], different types of Fe-S binding groups (carboxylate, hydroxamate, triazole, and thiol) were connected to the adenosine scaffold via methylene linkers of different length (1–5 carbons), as shown in Scheme 1. Fe-S binding groups functionalized with alkyl halide handles a – h were obtained or prepared in sufficient yield by N - or S -alkylation (Supporting Information: Synthesis of intermediates for 4a–4h and 8a–8h ).…”

“…Given the orientation of APS in the active site, we elected to functionalize the adenosine scaffold at the 5′-phosphate or exocyclic amine. Complex purification steps were avoided and nucleoside derivative throughput was increased using a solid-phase approach previously developed in our group [32]. Evaluation of the resulting compounds against Mtb APR indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated.…”

Development of nucleoside analogs under microwave irradiation

“…Paritala et al showed the use of microwave approach for the 5´-OH protection of ribonucleosides by tert-butyldimethylsilyl group (TBDMS) [8]. Microwave irradiation for 20 min in the presence of tert-butyldimethylsilyl chloride and imidazole gave the 5´-protected nucleoside 5 in quantitative yields.…”