Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 16, Issue 20, Pages 5265-5269Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.08.004
Keywords
macrocycle; click chemistry; Grb2 SH2 domain; cycloaddition; peptide mimetic
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Funding
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [N01CO12400, N01-CO-12400] Funding Source: Medline
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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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