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.
Stereoselective pyramidalization of free radicals by a vicinal fluorine substituent, the beta-fluorine effect, was invoked to rationalize a 77:23 anti/syn ratio of 2-deuterio-1-fluorocyclopentanes obtained by radical reduction of trans-2-fluoro-1-bromocyclopentane with tributyltin deuteride (Dolbier, W. R., Jr.; Bartberger, M. D. J. Org. Chem. 1995, 60, 4984-4985). We have evaluated analogous reductions of the four possible stereoisomers of some adenine 2'(3')-fluoro-3'(2')-O-phenoxythiocarbonyl nucleoside derivatives. In all cases, the steric effect of adenine on the beta face directs deuterium transfer from the stannane to C2'(C3') on the alpha face of the furanose ring. However, the beta-fluorine effect enhances ratios of deuterium transfer anti to the vicinal fluorine substituent.
Companioni, Dania, "Targeting of ribonucleotide reductase with 2'-Disulfide analogs of adenosine. Electronic versus steric effects in radical deoxygenation of fluorine-containing nucleosides" (2002 Fluorinated compounds are widely used in biochemistry, medicinal chemistry, and pharmacology. Synthesis of '-deoxy-'-fluoroadenosine and its arabino epimer as well as 3-deoxy-3'-fluoroadenosine and its xylo epimer were also targeted in order to study the electronic versus steric P-fluorine effects in radical deoxygenation of fluorine containing pentofuranose nucleosides. Our results clearly show that steric effect o f the heterocyclic base from the 3-face of the sugar is decisive, favoring the incorporation of deuterium from the less hindered c-face.
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