Synthesis and Biological Evaluation of Analogues of 5,8-Dideazaisofolic Acid (IAHQ) Modified at Positions 2, 4 and 9

The compound 5,8-dideazaisofolic acid (IAHQ), 1a, was found to posses modest antitumor activity against a variety of human and murine tumor cells both in vitro and in vivo. 1–5 Its lack of potency was attributed to slow influx into target cells as demonstrated with [3H] IAHQ in the presence of HCT-8 human colon adenocarcinoma cells in culture.6 The analogues 2-desamino-5,8-dideazaisofolic acid, 1b, and 2-desamino-2-methyl-5,8-dideazaisofolic acid, 1c, were prepared subsequently and found to be 6-and 44-fold more cytotoxic toward L1210 cells than 1a 7,8 This activity enhancement correlated well with increased affinity for the reduced folate transporter as measured by competition for the uptake of [3H] MTX into MOLT-4 cells.8