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

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-beta-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-beta-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-beta-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-beta-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-(beta-D-arabinofuranosyl)adenine. The nucleoside disulfides show modest cytotoxicity in a panel of human tumor cell lines.