8-substituted deazapterins

Silylation-amination of 6-acetoxymethyl-5-deazapterine 265 with NH3, HMDS 2, and TsOH for 120 h at 155-160°C in an autoclave affords, after subsequent trans-silylation with boiling methanol, the diamino compound 266 in 74% yield [76]. Silylation-amination-cychzation of the substituted 4-quinolone 267 gives the alkaloid isoaptamine hydrochloride 268 in 51% yield [77, 78] (Scheme 4.30). 

Errors of this magnitude make the useful prediction of free energies a difficult task, when differences of only one to three kcal/mol are involved. Nevertheless, within the error limits of the computed free energy differences, the trend is that relative to 8-methyl-N5-deazapterin or 8-methyl-pterin, the compounds methyl substituted in the 5, 6 or 7 positions are thermodynamically more stable when bound to DHFR largely by virtue of a hydrophobic effect, i.e. methyl substitution reduces the affinity of the ligand for the solvent more than it reduces affinity for the DHFR active-site. The stability of ligand binding to DHFR appears to be optimal with a 6-methyl substituent additional 5-methyl and/or 7-methyl substitution has little effect... 

Figure 4. Structures for cations (i.e. N3 protonated forms) of the 8-methyl substituted (a) N5-deazapterins and (b) pterins R5, R6 and R7 are either H or CH3.

A. D. Gorse and J. E. Gready, Molecular dynamics simulations of the docking of substituted N5-deazapterins to dihydrofolate reductase, Prot. Eng. 10 27 (1997). 

N3 protonated forms of 8-substituted N5-deazapterins in the active site of DHFR. Structures of the N8-protonated and neutral forms of 6-substituted-N5-deazapterins (e.g. 6-methyl-N5-deazapterin and N5-deazafolate) are shown in Figure 1. The structures of N3-protonated and neutral 6-R -8-R-N5-deazapterins (e.g. 6,8-dimethyl-N5-deazapterin) are shown in Figure 2. Both the 8-substituted (N3-protonated) and non-8-substituted (N8-protonated) cations are stabilized by the resonance-delocalized extended-guanidinium group. ... 

Cummins PL, Gready JE. Computer-aided drug design a free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase. J Comput-Aided Mol Des 1993 7 535-555. 

P. L. Cummins and J. E. Gready,/. Comput.-Aid. Mol. Des., 1, 535 (1993). Coraputei>Aided Drug Design A Free Energy Perturbation Study on the Binding of Methyl-Substituted Pterins and N5-Deazapterins to Dihydrofolate Reductase. 

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