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

Academic Article

Abstract

  • A series of 2[prime or minute]-thionucleosides, as potential inhibitors of ribonucleotide reductases, has been synthesized. Treatment of the 3[prime or minute],5[prime or minute]-O-TPDS-2[prime or minute]-O-(trifluoromethanesulfonyl)adenosine with potassium thioacetate gave the arabino epimer of 2[prime or minute]-S-acetyl-2[prime or minute]-thioadenosine which was deacetylated to give 9-(3,5-O-TPDS-2-thio-[small beta]-d-arabinofuranosyl)adenine in high yield. Treatment of the latter with diethyl azodicarboxylate-C(3)H(7)SH-THF gave 2[prime or minute]-propyl disulfide which was desilylated to give 9-(2-deoxy-2-propyldithio-[small beta]-d-arabinofuranosyl)adenine. Subsequent tosylation (O5[prime or minute]) and displacement of the tosylate with pyrophosphate afforded the 5[prime or minute]-O-diphosphate in a stable form as propyl mixed-disulfide, which upon treatment with dithiothreitol releases 9-(2-thio-[small beta]-d-arabinofuranosyl)adenine 5[prime or minute]-diphosphate. The arabino 2[prime or minute]-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[prime or minute]-mercapto disulfide bridge. The 2,6-diamino-, 2-amino-6-chloro- and 2-amino-6-methoxypurine ribosides were also converted to the corresponding 2[prime or minute]-deoxy-2[prime or minute]-propyldithio-[small beta]-d-arabinofuranosyl nucleosides, which might serve as convenient precursors to the arabino epimer of 2[prime or minute]-thioguanosine. Analogously, 2[prime or minute]-deoxy-2[prime or minute]-propyldithioadenosine was prepared from 9-([small beta]-d-arabinofuranosyl)adenine. The nucleoside disulfides show modest cytotoxicity in a panel of human tumor cell lines.
  • Keywords

  • Cell Line, Tumor, Enzyme Inhibitors, Formazans, Humans, Purine Nucleosides, Ribonucleotide Reductases, Thionucleosides
  • 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