version date: 1 December 2006 Dihydropholic acid Aminoe Trimetrexate Trimetrexate Piritrexim Piritrexim Fig 2 Superposition and comparisons of folate cofactor-derived antineoplastic drugs capable of inhibiting dhfr with the corresponding substrate Some physical similarities and differences among antineoplastic compounds (Table 1) belonging to groups I (TS)and VIl (DHFR)are illustrated, respectively, in Tables 2 and 3 Compared with substrates uridylate and thymidylate, both antimetabolites 5 fluorouracil and trifluridine show additional electronegative groups, which contribute to better nucleophilicity toward the thymidy late synthase target(Table 2). Fluorine is often considered an isostere of hydrogen even though it does not have the same valence as <www.iupac.org/publications/cd/medicinalchemistryl>7 Fig. 2 Superposition and comparisons of folate cofactor-derived antineoplastic drugs capable of inhibiting DHFR, with the corresponding substrate. Some physical similarities and differences among antineoplastic compounds (Table 1) belonging to groups I (TS) and VII (DHFR) are illustrated, respectively, in Tables 2 and 3. Compared with substrates uridylate and thymidylate, both antimetabolites 5- fluorouracil and trifluridine show additional electronegative groups, which contribute to better nucleophilicity toward the thymidylate synthase target (Table 2). Fluorine is often considered an isostere of hydrogen even though it does not have the same valence as Dihydropholic acid Aminopterin Trimetrexate Methotrexate Piritrexim Piritrexim Methotrexate Trimetrexate Aminopterin <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006