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Application of azide-alkyne cycloaddition 'click chemistry' for the synthesis of Grb2 SH2 domain-binding macrocycles

  1. Author:
    Choi, W. J.
    Shi, Z. D.
    Worthy, K. M.
    Bindu, L.
    Karki, R. G.
    Nicklaus, M. C.
    Fisher, R. J.
    Burke, T. R.

  2. Author Address

    NCI, Lab Med Chem, CCR, NIH, Frederick, MD 21702 USA. NCI, Lab Med Chem, CCR, NIH, Frederick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA.;Burke, TR, NCI, Lab Med Chem, CCR, NIH, Frederick, MD 21702 USA.;tburke@helix.nih.gov
    1. Year: 2006
    2. Date: Oct
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 16
    2. 20
    3. Pages: 5265-5269
  4. Type of Article: Article
  5. ISSN: 0960-894X
  1. Abstract:

    Copper (I) promoted [3+2] Huisgen cycloaddition of azides with terminal alkynes was used to prepare triazole-containing macrocycles based on the Grb2 SH2 domain-binding motif, 'Pmp-Ac(6)c-Asn', where Pmp and Ac(6)c stand for 4-phosphonomethyl-phenylalanine and I-aminocyclohexanecarboxylic acid, respectively. When cycloaddition reactions were conducted at 1 mM substrate concentrations, cyclization of monomeric units occurred. At 2 mM substrate concentrations the predominant products were macrocyclic dimers. In Grb2 SH2 domain-binding assays the monomeric (S)-Pmp-containing macrocycle exhibited a K-d value of 0.23 mu M, while the corresponding dimeric macrocycle was found to have greater than 50-fold higher affinity. The open-chain dimer was also found to have affinity equal to the dimeric macrocycle. This work represents the first application of 'click chemistry' to the synthesis of SH2 domain-binding inhibitors and indicates its potential utility. (c) 2006 Elsevier Ltd. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.bmcl.2006.08.004
  3. View record in Web of Science®
  4. WOS: 000241344400002

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