A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus.

摘要: Three lipophilic quinazoline-based aminomethyl pyridine compounds, which differ only in the position of nitrogen their ring, are described. CB300179 (2-pyridine), CB300189 (4-pyridine) and CB30865 (3-pyridine) all inhibited isolated mammalian TS with IC50 values 508, 250 156 nM respectively. was most potent growth inhibitory agent (IC50 range 1– 100 for several mouse human cell types). were active micromolar range. Against W1L2 cells, demonstrated reduced potency presence exogenous thymidine (dThd), against a W1L2:C1 overproducing line. In contrast, retained activity these systems. Furthermore, combinations precursors end products folate metabolism, e.g. dThd/hypoxanthine (HX) or leucovorin (LV), did not prevent activity. interfere incorporation tritiated dThd, uridine leucine after 4 h. A line raised acquired resistance to (W1L2:R865; > 200-fold), cross-resistant CB300189. addition, W1L2:R865 cells as sensitive parental agents from major chemotherapeutic drug classes. induced an S phase accumulation (preventable by co-administration dThd). No cycle redistribution observed following exposure (4–48 h) equitoxic concentration CB30865. NCI anticancer drug-discovery screen, displayed pattern consistent known anti-tumour agents. These data suggest that represents class potential novel mechanism action.