Design, synthesis, and anticancer activity of C8-substituted-4 '-thionucleosides as potential HSP90 inhibitors

Abstract

A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from D-ribose and D-mannose, respectively, employing Pummerer type or Vorbruggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100 mu M. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity. (C) 2016 Elsevier Ltd. All rights reserved.