version date: 1 December 2006 hydrogen. The atom is virtually the same size as hydrogen but more electronegative and thus can be used to vary the drug electronic properties without having any steric effect. Estimates of log P by using the fragment method show the greater fluorinated antimetabolites lipophilic character, as compared with the corresponding substrates(Table 2 ). Substituting fluorine for enzymically labile hydrogen can also disrupt the catalytic reaction since C-f bonds are not easily broken Table 2 Physicochemical similarities and differences of TS antimetabolites and substrate Molecular Dipol volume Compound Log P h bond h bond moment 2-Deoxyuridylate monophosphate 140.68 4.13 3.43 1.05 4.60 2-Deoxy-5-fluorouridylate monophosphate 140.33 -5.23 3.43 4.43 2-Deoxy-thymidylate monophosphate 147.58 1.053.05 2-Deoxy-5-trifluoromethyl-uridylate monophosphate(trifluridine MP) 16164 4.95 In contrast to the dihydrofolate substrate the methotrexate antagonist has an extra pteridine ring amino group, which improves the hydrogen bond interaction on the active site The replacement of the 4-oxo group of the substrate by the amino group will not appreciably change the size of the analog, but will have a marked effect on its polarity, electronic distribution, and bonding (Table 3). However, the N-methyl group containing methotrexate antagonist has a different shape and increased log P constant and liposolubility The methyl roup that generated steric hindrance may create constraints and impose particular favorable conformations for ligand and receptor interactions. Moreover, the N-methyl group inductive electron-donating effect disfavors ionization and gives rise to non-ionized forms, less soluble in water [71 <www.iupac.org/publications/cd/medicinalchemistry/> 88 hydrogen. The atom is virtually the same size as hydrogen but more electronegative and thus can be used to vary the drug electronic properties without having any steric effect. Estimates of log P by using the fragment method show the greater fluorinated antimetabolites lipophilic character, as compared with the corresponding substrates (Table 2). Substituting fluorine for enzymically labile hydrogen can also disrupt the catalytic reaction since C–F bonds are not easily broken [6]. Table 2 Physicochemical similarities and differences of TS antimetabolites and substrate. Compound Molecular volume (cm3 /mol) Log P (fragments) H bond acceptor H bond donor Dipole moment (debyes) 2'-Deoxyuridylate monophosphate 140.68 –4.13 3.43 1.05 4.60 2'-Deoxy-5-fluorouridylate monophosphate 140.33 –5.23 3.43 1.05 4.43 2'-Deoxy-thymidylate monophosphate 147.58 –3.48 3.44 1.05 3.05 2'-Deoxy-5-trifluoromethyl-uridylate monophosphate (trifluoridine MP) 161.64 –3.24 3.59 1.05 4.95 In contrast to the dihydrofolate substrate, the methotrexate antagonist has an extra pteridine ring amino group, which improves the hydrogen bond interaction on the active site. The replacement of the 4-oxo group of the substrate by the amino group will not appreciably change the size of the analog, but will have a marked effect on its polarity, electronic distribution, and bonding (Table 3). However, the N-methyl group containing methotrexate antagonist has a different shape and increased log P constant and liposolubility. The methyl group that generated steric hindrance may create constraints and impose particular favorable conformations for ligand and receptor interactions. Moreover, the N-methyl group inductive electron-donating effect disfavors ionization and gives rise to non-ionized forms, less soluble in water [7]. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006