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

Organic & Biomolecular Chemistry Pub Date: 2003-11-20 DOI: 10.1039/B311504F

Abstract

A series of 2′-thionucleosides, as potential inhibitors of ribonucleotide reductases, has been synthesized. Treatment of the 3′,5′-O-TPDS-2′-O-(trifluoromethanesulfonyl)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.

Graphical abstract: 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
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