A combinatorial method for solution-phase synthesis of labeled bivalent beta-turn mimics.
Piperidine-functionalized, 1,4-disubstituted-1,2,3-triazoles of generic structure 1 were conceived as "minimalist" mimics of peptidic beta-turn structures. Key features of these molecules include (i) the possibility of incorporating amino acid side chains corresponding to many of the protein amino acids; (ii) a close correspondence of separations of these side chains to i + 1 to i + 2 residues in turns; (iii) facile adjustment of the side-chain vectors on docking while only influencing two critical degrees of freedom; and (iv) some electrostatic polarity. Fifteen monomers of this type were made via copper-mediated cycloaddition reactions. Solution-phase methodologies were devised to assemble these monomers into bivalent compounds in high purity states (typically >85%) so that they could be used in first-pass biological assays without further purification. The skeleton for forming these bivalent compounds is triazine-based. There is a third site which allowed for introduction of a fluorescent label (library of compounds 2) or an alkyne-functionalized triethylene glycol chain (library of compounds 3) included to promote water-solubility and to allow incorporation of probes via copper-mediated cycloaddition reactions. In the event, two 135-membered libraries were prepared, one consisting of compounds 2 and the other of 3. No protecting groups or coupling agents were required; these attributes of the method were important to allow most of the products to be obtained in over 85% purities. The fluorescein-tagged library of compounds 2 was screened in a fluorescence-activated cell sorting (FACS) assay using cells transfected to overexpress one of the following neurotrophin receptors: TrkA, TrkC, and p75. Preliminary findings indicate four compounds 2gm, 2gn, 2gi, and 2gj bound the TrkA receptor selectively; all of these contain a threonine-lysine turn mimic. Thus, a pharmacological probe for the TrkA receptor has been developed.
Angell
Yu
Y
Department of Chemistry, Texas A & M University, Box 30012, College Station, Texas 77841, USA.
Chen
Dianjun
D
Brahimi
Fouad
F
Saragovi
H Uri
HU
Burgess
Kevin
K
D000818:Animals; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019281:Dimerization; D006801:Humans; D008239:Lysine / Q000737:chemistry; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D020917:Receptor, trkA / Q000737:chemistry*; D012996:Solutions; D013912:Threonine / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
D010455:Peptides; D012996:Solutions; D014230:Triazoles; D013912:Threonine; D020917:Receptor, trkA; D008239:Lysine