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. 2010 Jul 20;15(7):4961-83.
doi: 10.3390/molecules15074961.

Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit

William L Scott  1 , Ziniu Zhou, Paweł Zajdel, Maciej Pawłowski, Martin J O'Donnell
Affiliations

Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit

William L Scott et al. Molecules. .

Abstract

Amino acids are Nature's combinatorial building blocks. When substituted on both the amino and carboxyl sides they become the basic scaffold present in all peptides and proteins. We report a solid-phase synthetic route to large combinatorial variations of this fundamental scaffold, extending the variety of substituted biomimetic molecules available to successfully implement the Distributed Drug Discovery (D3) project. In a single solid-phase sequence, compatible with basic amine substituents, three-point variation is performed at the amino acid a-carbon and the amino and carboxyl functionalities.

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Figures

Figure 1
Figure 1
Important molecules containing the fundamental peptide unit 1.
Scheme 1
Scheme 1
Synthetic route to amino- and carboxyl-substituted unnatural amino acids.
Scheme 2
Scheme 2
Synthetic pathways A and B to compounds 3.
Scheme 3
Scheme 3
Synthesis of multiply-substituted 2 where R3 contains a nucleophilic site.
See this image and copyright information in PMC

References

    1. Scott W.L., O’Donnell M.J. Distributed drug discovery, part 1: Linking academia and combinatorial chemistry to find drug leads for developing world diseases. J. Comb. Chem. 2009;11:3–13. doi: 10.1021/cc800183m. - DOI - PMC - PubMed
    1. Scott W.L., Alsina J., Audu C.O., Babaev E., Cook L., Dage J.L., Goodwin L.A., Martynow J.G., Matosiuk D., Royo M., Smith J.G., Strong A.T., Wickizer K., Woerly E.M., Zhou Z., O’Donnell M.J. Distributed drug discovery, part 2: Global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D3 catalog construction. J. Comb. Chem. 2009;11:14–33. doi: 10.1021/cc800184v. - DOI - PMC - PubMed
    1. Scott W.L., Audu C.O., Dage J.L., Goodwin L.A., Martynow J.G., Platt L.K, Smith J.G., Strong A.T., Wickizer K., Woerly E.M., O’Donnell M.J. Distributed drug discovery, part 3: Using D3 methodology to synthesize analogs of an anti-melanoma compound. J. Comb. Chem. 2009;11:34–43. doi: 10.1021/cc800185z. - DOI - PMC - PubMed
    1. O'Donnell M.J., Zhou C., Scott W.L. Solid-phase unnatural peptide synthesis (UPS) J. Am. Chem. Soc. 1996;118:6070–6071. doi: 10.1021/ja9601245. - DOI
    1. Scott W.L., Martynow J.G., Huffman J.C., O’Donnell M.J. Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates. J. Am. Chem. Soc. 2007;129:7077–7088. doi: 10.1021/ja069188y. - DOI - PubMed

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