Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity

摘要: The transport properties and growth-inhibitory potential of 37 classic novel antifolate compounds have been tested in vitro against human murine cell lines expressing different levels the reduced folate carrier (RFC), membrane-associated binding protein (mFBP), or both. intracellular targets these drugs were dihydrofolate reductase (DHFR), glycinamide ribonucleotide transformylase (GARTF), folylpolyglutamate synthetase (FPGS), thymidylate synthase (TS). Parameters that investigated included affinity both folate-transport systems for drugs, their as a function cellular RFC/mFBP expression, protective effect either FA leucovorin growth inhibition. Methotrexate, aminopterin, N10-propargyl-5,8-dideazafolic acid (CB3717), ZD1694, 5,8-dideazaisofolic (IAHQ), 5,10-dideazatetrahydrofolic (DDATHF), 5-deazafolic (efficient substrate FPGS) used basic structures present study, from which modifications introduced pteridine/quinazoline ring, C9-N10 bridge, benzoyl glutamate side chain. It was observed RFC exhibited an efficient all analogues except CB3717, 2-NH2-ZD1694, side-chain-modified FPGS inhibitors. Substitutions at 2-position (e.g., 2-CH3) improved methotrexate aminopterin. Other good substrates PT523 (N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine), 10-ethyl-10-deazaaminopterin, DDATHF. With respect to mFBP, N-3 4-oxo positions resulted substantial loss affinity. Modifications other sites molecule well tolerated. Growth-inhibition studies identified series preferentially transported via (2,4-diamino structures) mFBP (CB3717, 2-NH-ZD1694, acid), whereas efficiently pathways DDATHF, BW1843U89, LY231514). Given fact increasing number normal neoplastic cells tissue, expression are being recognized, this antagonist structure-activity relationship can be value predicting drug sensitivity resistance tumor drug-related toxicity rational design development antifolates.