The reaction of melphalan with deoxyguanosine and deoxyguanylic acid

Abstract

The reaction of melphalan (phenylalanine mustard, I) with 2′-deoxyguanosine, followed by removal of the sugar in acid, yielded two products. The major product was identified as 4-( N-(2-guanin-7-ylethyl)- N-(2-hydroxyethyl)amino)phenylalanine (II) by ultra-violet absorption, mass and NMR spectroscopy. The minor product has already been identified as the corresponding bis-guaninyl adduct III (Tilby et al., Chem.-Biol. Interact., 73 (1990) 183–194). The reaction of melphalan with 5′-deoxyguanylic acid yielded the deoxyribonucleotide of II and products resulting from reaction with the phosphate group. The initial products, which were formed with a half-life of ∼40 min at 37°, still had a reactive chloroethyl group; this was displaced more slowly, by reaction with water or with another molecule of dGMP. The products of reaction of melphalan with DNA were released by treatment with acid (0.1 M HCl, 70°, 30 min) and separated from each other on a cation exchange column. They were identified as II, III and an adenine adduct, in a ratio of approximately 3:1:2.