Synthesis of classical, three-carbon-bridged 5-substituted furo2,3-dpyrimidine and 6-substituted pyrrolo2,3-dpyrimidine analogues as antifolates

摘要

Bridge homologation of the previously reported classical two-carbon-bridged antifolates, a 5-substituted 2,4-diaminofuro2,3-dpyrimidine (1) which is a 6-regioisomer of LY231514 (Alimta) and a 6-subsituted 2-amino-4-oxopyrrolo2,3-dpyrimidine, afforded the three-carbon-bridged antifolates analogues 4 and 5, with enhanced inhibitory activity against tumor cells in culture (EC50 values in the 10(-8)-10(-7) M range or less). These two analogues were synthesized via a 10-step synthetic sequence starting from methyl 4-bromobenzoate (14), which was elaborated to the a-chloromethyl ketone (8) followed by condensation with 2,6-diaminopyrimidin-4-one (7) to afford the substituted furo2,3-dpyrimidine 9 and the pyrrolo2,3-dpyrimidine 10. Subsequent coupling of each regioisomer with diethyl-L-glutamate followed by saponification afforded 4 and 5. The biological results indicate that elongation of the C8-C9 bridge of the classical 5-substituted 2,4-diaminofuro2,3-dpyrimidine and 6-substituted 2-amino-4-oxopyrrolo2,3-dpyrimidine are highly conducive to antitumor activity in vitro, despite a lack of increase in inhibitory activity against the target enzymes. This supports our original hypothesis that truncation of the B-ring of a highly potent 6-6 ring system to a 6-5 ring system can be compensated by bridge homologation to restore the overall length of the molecule.