Nucleoside analogues. Part 10. Synthesis of three unusual 5-fluorouracil seco-nucleosides incorporating N-(2-chloroethyl)-N-nitrosourea residues

Abstract

Seco-nucleosides in which 5-fluorouracil (5-FU) is attached at N³ cannot be synthesised when the heteroatom is O by the methods effective when it is S. An N-phthaloyl representative of this class has now been made from a suitably protected pyrimidine and converted into the corresponding N-(2-chloroethyl)-N-nitrosourea (CNU), a molecular combination of anti-tumour drugs of great interest for comparison with other closely related structures. Further, the successful manipulation of the carboxy group in the standard synthetic scheme has led to the preparation of the first molecular combination incorporating this function. Thirdly, hydrazinolysis of phthalimido-CNU's has made possible the construction of complex drugs with both CNU and MNU (N-methyl-N-nitrosourea) moieties, thus achieving regiospecific location of two N-nitroso groups in molecules with four dissimilar urea NH's. All these drugs are undergoing anti-tumour evaluation, the effect of the CNU-MNU combinations on a repair enzyme of DNA metabolism being of additional significance.