DAMP-ES

The crystal structure of 2-amino-4-oxo-6-adamantylpteridine (DOPT), a folate analog of the potent lipophilic antifolate, 2,4-diamino-6-adamantylpteridine (DAPT), which is selective for mammalian dihydrofolate reductase (DHFR), was determined to examine its conformational features and to define its mode of binding to the enzyme DHFR.DOPT crystallized as an ethanesulfonate salt in the monoclinic space group P2₁/c with cell dimensions a = 20.261 (7) Å, b = 16.357 (2) Å, c = 12.317 (3) Å, β = 93.76 (2)°, and Z = 8.The pteridine ring is protonated at N(1) to form the ethanesulfonate salt.A theor. study of the binding characteristics of the folate, DOPT, the antifolate model, DAPT, and the pyrimidine analog, 2,4-diamino-5-adamantyl-6-methylpyrimidine, DAMP, to both chicken and Lactobacillus casei DHFR was carried out with YETI, a mol. mechanics program which optimized the DHFR-inhibitor interactions.The objective of these calculations was to determine characteristics of binding that would aid in explaining the species specificity and selectivity of DAMP and DAPT.These studies indicate that there is a correlation between the size of a specific enzyme active site and antifolate activity, i.e., the antifolates DAPT and DAMP have more unfavorable intermol. interactions in the bacterial enzyme than in chicken liver DHFR, consistent with their biol. activity.These studies further indicate that DOPT, the oxidized analog of DAPT, is not likely to bind in the folate orientation.

The photosensitized oxygenation of 5‐aryl‐2,4‐diaminopyrimidines 1 in protic solvent led to the formation of the new 4‐amino‐1,3‐5‐triazin‐2‐yl ketones 2 in high yields. The structures of 2 were elucidated by spectroscopical means, especially by 13C‐NMR and UV data. Photooxygenation of 2,4‐diamino‐5‐(p‐chlorophenyl)‐6‐ethylpyrimidine 1a under reductive conditions, e.g. In the presence of excess NaBH4, gave 2‐amino‐5‐(p‐chlorophenyl)‐t‐6‐ethyl‐5,6‐dihydro‐r‐5‐hydroxy‐4(3H)‐pyrimidinone (4a), the structure of which was determined by X‐ray analysis. In the proposed mechanisms for both types of reactions, the dipolar ion 5 is assumed to be a common intermediate. For the new efficient synthesis of 1,3,5‐triazines from 2,4‐diaminopyrimidines, a 5‐aryl substituent seems to be essential.