Deazapterins

The UV spectra have been used in studies of protonation and related covalent hydration, structural assignments and tautomerism (see appropriate Sections), as well as in studies of bridgehead addition to 5-deazapterins (79MI21500, 78TL2271) and related 5-deazaflavin derivatives (80JA1092). 

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). 

Cyclocondensation of (pivaloylamino)-(methylthio)azapterin 305 with 1-morpholinocyclopentene 306 gave 5,6-cyclopenteno-5-deazapterin 307 (87H2673). 

Figure 1. Structures for (a) the stable cation showing the extended guanidinium resonance, and (b) the neutral form of 6-R -N5-deazapterins. In the inhibitor N5-deazafolate, the side chain is R = methylene(p-aminobenzoyl)-L-glutamate.

For molecules and molecular ions, such as the cations of 8-methyl-N5-deazapterin and 8-methyl-pterin, the charge distribution (which is represented in MD simulations by a set of discrete atomic charges) will be dependent on the chosen quantum chemical model. Differences in the charge distributions of these cations may influence both the relative binding and solvation thermodynamics. Consequently, we studied the relative solvation thermodynamics of similar DHFR-binding molecular ions.30 Atomic charges... 

Table 1. Dependence of free energies (kcal/mol) on the residue-based cutoff radii Rc (A) for generation of cation-solvent (c-s) and solvent-solvent (s-s) interaction lists. Free energy changes are given for the forward AGf (i.e. 8-methyl-N5-deazapterin — 8-methyl-pterin) and reverse AGr mutations of the electrostatic terms. ...

Table 3. Free energy changes (kcal/mol) calculated for the mutation 6,8-dimethyl-N5-deazapterin — 6-methyl-N5-deazapterin in solution. Results for 80 ps simulation, with 200 ps...

Figure 3. Correlation between the calculated A AG bind values (Table 4) and the N8-0 distances (where O is the carbonyl oxygen of the conserved Ile/Leu residue in the active site of DHFR) in the 6-methyl-N5-deazapterin MD complexes.

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.

Table 5. Free energies (kcal/mol) relative to 8-methyl-N5-deazapterin...

UCW = capped water, TW = tethered water (see text), k = force constant for restraining potential (kcal/mol/A2). b Radius (A) of solvation sphere. 1 Numbers of dynamical water molecules within solvation sphere. d Mean and standard error for the forward (i.e. 8-methyl-N5-deazapterin —> 8-methylpterin) and reverse mutation of the electrostatic force field Cutoff for protein-ligand and solvent-ligand interaction all other interactions are subject to a 9 A cutoff. 

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