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

A series of 2prime or minute]-thionucleosides, as potential inhibitors of ribonucleotide reductases, has been synthesized. Treatment of the 3prime or minute],5prime or minute]-O-TPDS-2prime or minute]-O-(trifluoromethanesulfonyl)adenosine with potassium thioacetate gave the arabino epimer of 2prime or minute]-S-acetyl-2prime 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 2prime or minute]-propyl disulfide which was desilylated to give 9-(2-deoxy-2-propyldithio-small beta]-d-arabinofuranosyl)adenine. Subsequent tosylation (O5prime or minute]) and displacement of the tosylate with pyrophosphate afforded the 5prime 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 5prime or minute]-diphosphate. The arabino 2prime 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 Cys439-2prime 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 2prime or minute]-deoxy-2prime or minute]-propyldithio-small beta]-d-arabinofuranosyl nucleosides, which might serve as convenient precursors to the arabino epimer of 2prime or minute]-thioguanosine. Analogously, 2prime or minute]-deoxy-2prime 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.