80082-66-2

A distinguishing character of human mammary cancer, vis a vis the normal gland, is its capacity to sulfoconjugate estrogens.The title compounds (4 and 12), which are multisubstrate analogues of a putative enzyme-bound transition state of estrogen sulfation (sulfurylation), were synthesized in search of specific chemotherapeutic agents for the treatment of human mammary cancer. 4-Nitroestrone 3-O-(ω-alkyl) ethers (3a), obtained in 69-73percent yield on treatment of 4-nitroestrone (2a) with an α,ω-dibromoalkane and NaH in Me2SO, reacted with adenine in THF containing TBAF to give the corresponding 9-alkyladenine (4a-c), in 55-60percent yield.Reaction of 9-(3-chloropropyl)adenine (5) and estrone (2b) yielded a compound (4d) identical with the major product of the interaction of estrone 3-O-(3-bromopropyl) ether (3d) and adenine.The structures of 4a-d are thereby established.The preparation of the adenosine methylene-bridged estrogens (12a,b) first required the 5-O-alkylation of methyl 2,3-O-isopropylidene-5-O-triflyl-β-D-ribofuranoside (7) with the 4-nitroestrone 3-O-(ω-hydroxyalkyl) ethers, 6a,b.The 5-substituted ribofuranosides (8a,b) were converted to the corresponding ribofuranose derivatives (9a,b) in 50percent yield in refluxing aqueous acetic acid.Treatment of 9a,b with acetic anhydride in pyridine gave the corresponding 1,2,3-tri-O-acetate derivatives (10a,b), which reacted with adenine in acetonitrile and SnCl4 to give the β-nucleoside 2',3'-di-O-acetates, 11a,b, respectively.Saponification of the latter with NH3/CH3OH gave 12a,b.Compounds 4a-d and 12a,b showed weak to modest inhibition of estrone sulfurylation as mediated by purified bovine adrenal estrogen sulfotransferase.However, 4a,c and 12a,b exhibited significant growth inhibition of the breast cancer cell line MCF-7 and P388 murine leukemia cells.

Methyl 2,3-O-isopropylidene-5-O-triflyl-β-D-ribofuranoside (2) reacts at room temperature with primary aralkanols such as benzyl alcohol and the steroid alcohols 3a,b in dichloromethane and in the presence of sodium sulfate to give the corresponding aralkyl 2,3-O-isopropylidene-5-O-methyl-β-D-ribofuranosides 5a,b and 11 in 40-45percent yields.Migration of the methoxyl group from C-1 to C-5, via a tricyclic oxonium ion (7a), is suggested as the basis of formation of the new β-glycoside.Anchimeric assistance by a benzyloxy group in the displacement of the sulfonate is observed in the reaction of benzyl 2,3-O-isopropylidene-5-O-triflyl-β-D-ribofuranoside (14) with methanol, which affords methyl 5-O-benzyl-2,3-O-isopropylidene-β-D-ribofuranoside (15) in 40percent yield on treatment with Na2SO4 in CH2Cl2.The elements of anomeric control in these facile transformations remain to be elaborated.