Synthesis and cytotoxicity of 9-(2-deoxy-2-alkyldithio-β-D-arabinofuranosyl)purine nucleosides which are stable precursors to potential mechanistic probes of ribonucleotide reductases

Academic Article

Abstract

  • A series of 2′-thionucleosides, as potential inhibitors of ribonucleotide reductases, has been synthesized. Treatment of the 3′,5′-O-TPDS-2′-O-(trifluóromethanesulfonyl)adenosine with potassium thioacetate gave the arabino epimer of 2′-S-acetyl-2′-thioadenosine which was deacetylated to give 9-(3,5-O-TPDS-2-thio-β-D-arabinofuranosyl)adenine in high yield. Treatment of the latter with diethyl azodicarboxylate-C3H7SH-THF gave 2′-propyl disulfide which was desilylated to give 9-(2-deoxy-2-propyldithio-β-D-arabinofuranosyl)adenine. Subsequent tosylation (O5′) and displacement of the tosylate with pyrophosphate afforded the 5′-O-diphosphate in a stable form as propyl mixed-disulfide, which upon treatment with dithiothreitol releases 9-(2-thio-β-D-arabinofuranosyl)adenine 5′-diphosphate. The arabino 2′-mercapto group might interact with the crucial thiyl radical at cysteine 439 leading to the inhibition of ribonucleotide reductases via formation of a Cys439-2′-mercapto disulfide bridge. The 2,6-diamino-, 2-amino-6-chloro- and 2-amino-6-methoxypurine ribosides were also converted to the corresponding 2′-deoxy-2′-propyldithio-β-D-arabinofuranosyl nucleosides, which might serve as convenient precursors to the arabino epimer of 2′-thioguanosine. Analogously, 2′-deoxy-2′-propyldithioadenosine was prepared from 9-(β-D-arabinofuranosyl)-adenine. The nucleoside disulfides show modest cytotoxicity in a panel of human tumor cell lines.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 10096894
  • Author List

  • Wnuk SF; Lewandowska E; Companioni DR; Garcia PI; Secrist JA
  • Start Page

  • 120
  • End Page

  • 126
  • Volume

  • 2
  • Issue

  • 1