Crystallographic studies of the antineoplastic antifolate 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine...

The lipid-soluble diaminopyrimidine, 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) binds tightly to dihydrofolate reductase and has antineoplastic activity in man and several animal systems. The x-ray crystal structure of this antifolate, as the ethanesulfonate salt, was studied to investigate the conformational aspects of its binding specificity. The molecular conformation shows the dichlorophenyl ring nearly perpendicular (phi = 110 degrees) to the pyrimidine ring which is coplanar with its 2,4,6-substituents. the protonated N1 atom of the pyrimidine ring forms a hydrogen bond to an ethanesulfonate oxygen, as do both N2 and one of N4 hydrogens. The other N4 hydrogen participates in an inversion related base-pair type of hydrogen bond with N3 of a neighboring molecule, similar to patterns observed in other diaminopyrimidine antifolates.