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Nucleoside analogs. 14. The synthesis and antitumor activity in mice of molecular combinations of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea moieties separated by a three-carbon chain

par McElhinney, Stanley R.S.;McCormick, Joan J.E.;Bibby, Mike M.C.;Double, John J.A.;Radacic, Marco;Dumont, Patrick
Référence Journal of medicinal chemistry, 39, 7, page (1408-1412)
Publication Publié, 1996-03

Article révisé par les pairs

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Résumé :

5-Fluorouracil (5-FU) seco-nucleosides having as the 'sugar' moiety a two- carbon (C 2) side chain carrying a N-(2-chloroethyl)-N-nitrosourea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast enough for significant contribution to the high activity they showed against colon and breast tumors in mice. In the present study of the synthesis of the more reactive C 3 seco- nucleosides, it emerged that, of various groups attached to the aldehydic center in the precursor phthalimides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relatively large amounts of reagent methanethiol, and exploration of alternatives involving α-chlorination of alkyl methyl sulfide or Pummerer rearrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields. For successful preparation of the alkoxy/uracil-3-yl compounds, the route used for C 2 homologs required considerable experimental modification. In addition to these O,N- and S,N-acetals, some N,N-acetals bearing two 5-FU residues were prepared. The new drugs have been tested against a panel of experimental tumors in mice. Although it is evident from a parallel study that even these C 3 seco-nucleosides release free 5-FU too slowly in vivo, several of them have shown impressive anticancer activity. Reviewing their performance in comparison with earlier molecular combinations, a short list of seven [B.4152 (6), B.4015 (5), B.4030 (10), B.3999 (4), B.3995 (2), B.4083 (3), and B.3996 (the N 3-substituted analog of 1)] should be investigated further. This is particularly appropriate in light of the present understanding of the mode of action of chloroethylating agents. Following a prolonged period of clinical impatience with nitrosoureas because of limited selectivity of action, a new era is confidently anticipated as these powerful drugs are increasingly studied in combination with O 6-benzylguanine and other more efficient inhibitors of repair enzymes like O 6-alkylguanine-DNA-alkyltransferase now being developed.