S. Wei et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5543–5546
5545
Figure 2.
sized.19 Following our previous procedure, the terminal free amines
were coupled with N,N-dimethyl- -phenylalanine using water
Figure 3. Calculated structure of the G0-4-Me2 dendrimer in tube version which
indicates the tight packing around the pyridoxamine group. The pyridoxamine and
surrounding N,N-dimethyl-L-phenylalanine residues are presented as space-filling
models. As can be seen, the amino and hydroxyl groups are exposed to solvent, and
to dimethylamino groups.
L
soluble 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholini-
um chloride (DMTMM) as a coupling reagent.20 Finally, the Boc
group was removed by 1 N HCl, and the resulting free pyridoxamine
was subjected to the next transamination studies. All the final pyri-
doxamine dendrimers were completely water soluble. The pyridox-
amine’s characteristic peak at 318 nm in the UV–vis spectrum was
observed for all the deprotected dendrimers. The structure of the
first generation (Fig. 2) is shown as G0-1-Me2.
therefore promotes asymmetrical transamination favoring the for-
mation of L-isomers. In comparison to the single thioether dendri-
mers,14 a slight decrease in the ee value of transamination reaction
was observed.
The concentrations of the dendrimers’ water solutions were ad-
justed to ca. 5.0 ꢀ 10ꢁ3 M by comparing the intensity of the UV–vis
spectrum at 318 nm with the absorption of a standard solution of
pyridoxamine. The transamination reactions were run between
Our new dendrimers synthesized from two starting points sup-
port the dense core model of dendrimer structures in solution,
where the flexible chains can fold back to fill otherwise empty
space. The observed catalysis and chiral induction by formally fur-
ther away residues, coupled with our previous results, demon-
strate that even a dendrimer with catalytic groups formally
remote from the pyridoxamine unit is a good mimic of some as-
pects of transaminase enzymes.
This shows how flexible dendrimers are, and how far from the
formal tree structure they really can exist. They share this flexible
folding with proteins. Thus it greatly expands the potential for den-
drimers to serve as multifunctional catalysts and reactants.
dendrimers (ca. 5.0 ꢀ 10-3 M) and
a
-keto acids (5.0 ꢀ 10ꢁ2 M) at
pH 7.5, t = 20–25 °C. The resulting amino acids, after derivatization
with o-phthalaldehyde and N-Ac-L-cysteine, were analyzed with
reverse-phase HPLC. The final results are summarized in Table 1.
It is striking that the largest effects were seen with the dendri-
mers having the longest arms and therefore in principal with chiral
catalytic groups furthest from the core (but not if they fold back!).
Molecular modeling studies were performed to further under-
stand the enantioselectivity of transamination within the dendri-
mers. The calculations were executed using MMFF’s force field in
the presence of the GB/SA continuum water model to simulate
the real aqueous system. The resulting structure of G0-4-Me2 is de-
picted in Figure 3, in which tight packing was observed near the
pyridoxamine residue. The strong hydrophobic interaction among
the side chains as well as multiple intramolecular hydrogen bonds
lock the two thioether arms mostly on one side of the pyridox-
amine core. Also, the combination of these interactions holds the
pyridoxamine residue within the chiral environment generated
Acknowledgments
This work was supported by a grant from the NSF. S.V. was sup-
ported by a summer REU Fellowship.
References and notes
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by the proximate terminal N,N-dimethyl-L-phenylalanine, and
Table 1
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2005, 15, 1351.
The % ee values of the L-amino acids formed in the transamination reactions between
dendrimers and phenylpyruvic acid or pyruvic acid in aqueous mediaa–c
Dendrimer
Phenylpyruvic acid
Pyruvic acid
G0-1-Me2
G0-2-Me2
G0-3-Me2
G0-4-Me2
20.3
24.9
26.7
34.5
16.7
27.1
29.7
33.2
10. Breslow, R.; Bandyopadhyay, S.; Levine, M.; Zhou, W. J. Chembiochem 2006, 7,
1491.
a
All% ee values are averaged from two or three trials, and agreed within ca. 3%.
11. Bandyopadhyay, S.; Zhou, W.; Breslow, R. Org. Lett. 2007, 9, 1009.
12. Chruma, J. J.; Liu, L.; Zhou, W. J.; Breslow, R. Bioorg. Med. Chem. 2005, 13, 5873.
13. Liu, L.; Zhou, W. J.; Chruma, J.; Breslow, R. J. Am. Chem. Soc. 2004, 126, 8136.
14. Breslow, R.; Wei, S.; Kenesky, C. Tetrahedron 2007, 63, 6317.
15. Kuzuhara, H.; Iwata, M.; Emoto, S. J. Am. Chem. Soc. 1977, 99, 4173.
b
Transamination reaction conditions: dendrimers (ca. 5.0 ꢀ 10ꢁ3 M),
a-keto acids
(5.0 ꢀ 10ꢁ2 M), EDTA (1.0 ꢀ 10ꢁ2 M), pH 7.5, t = 20–25 °C.
c
The amino acid products were derivatized by o-phthalaldehyde and N-Ac-L-cys-
teine before analysis by reverse-phase HPLC.