Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis

Abstract

Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…Because of the different N -nitroso positions, the reaction of different compounds would give different decompositions of isocyanates and diazohydroxides, as shown in Scheme . The normal C5‘-CENU analogs 732 and 751 were the most cytoactive of the C5‘-series, with % ILS values of 135 and 191, respectively (Table ). , The inactive 752 would yield the same isocyanate but a different diazohydroxide than 751 (Scheme a,b). This fact supports the role of alkylation, and not carbamoylation, in the anticancer activity of N -nitrosourea drugs.…”

“…The compounds 753 − 761 were prepared 533,536 from the corresponding 5‘-ribofuranuronic acids, , as outlined in Scheme . Spacer arms were used to place the N -nitrosoureido group at different distances from the C5‘-position . The reaction of the 5‘-acid with diphenylphosphoryl azide and triethylamine formed a mixed anhydride which, in turn, reacted smoothly with either aminoethylureas or with anilinoureas to yield the desired urea intermediates. , N -Nitrosation was effected either by the use of sodium nitrite in concentrated formic acid or by means of the CENU transfer agent 11e for 751 and its ethyl analog for 752 .…”

“…Spacer arms were used to place the N -nitrosoureido group at different distances from the C5‘-position . The reaction of the 5‘-acid with diphenylphosphoryl azide and triethylamine formed a mixed anhydride which, in turn, reacted smoothly with either aminoethylureas or with anilinoureas to yield the desired urea intermediates. , N -Nitrosation was effected either by the use of sodium nitrite in concentrated formic acid or by means of the CENU transfer agent 11e for 751 and its ethyl analog for 752 . Nitrosation of the N3-methylureas produced the N3-nitroso products 753 , 754 , 757 , 758 , and 760 , whereas the same nitrosation of the N3-cyclohexyl ureas yielded the N1-nitroso products 755 , 756 , and 761 .…”

“…Further attempts were made 533,536 to exploit the carbamoylating potential of the N-nitrosourea moiety at the C5′-position as irreversible inhibitors of the active site of nucleotide-metabolizing enzymes. Molecular modeling revealed 533 that for effective binding with the active site, the reactive group, i.e.…”

“…The compounds 753-761 were prepared 533,536 from the corresponding 5′-ribofuranuronic acids, 537,538 as outlined in Scheme 73. Spacer arms were used to place the N-nitrosoureido group at different distances from the C5′-position.…”