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 3-CARBON CHAIN

5-Fluorouracil (5-FU) seco-nucleosides having as the ''sugar'' moiety a two-carbon (C-2) Side chain carrying a N-(2-chloroethyl)-N-nitrosour ea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast en ough for significant contribution to the high activity they showed aga inst colon and breast tumors in mice. In the present study of the synt hesis of the more reactive C-3 seco-nucleosides, it emerged that, of v arious groups attached to the aldehydic center in the precursor phthal imides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relati vely large amounts of reagent methanethiol, and exploration of alterna tives involving a-chlorination of alkyl methyl sulfide or Pummerer rea rrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields. For successful pre paration of the alloxyl/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 resid ues were prepared. The new drugs have been tested against a panel of e xperimental tumors in mice. Although it is evident from a parallel stu dy that even these C-3 seco-nucleosides release free 5-FU too slowly i n vivo, several of them have shown impressive anticancer activity. Rev iewing their performance in comparison with earlier molecular combinat ions, a short list of seven [B.4152 (6), B.4015 (5), B.4030 (10), B.39 99 (4), B.3995 (2), B.4083 (3),:and B.3996 (the N-3-substituted analog of 1)] should be investigated further. This is particularly appropria te in light of the present understanding of the mode of action of chlo roethylating agents. Following a prolonged period of clinical impatien ce with nitrosoureas because of limited selectivity of action, a new e ra is confidently anticipated as these powerful drugs are increasingly studied in combination with O-6-benzylguanine and other more efficien t inhibitors of repair enzymes like O-6-alkylguanine-DNA-alkyltransfer ase now being developed.