Application of azide-alkyne cycloaddition 'click chemistry' for the synthesis of Grb2 SH2 domain-binding macrocycles.
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-phosphonomethylphenylalanine and 1-aminocyclohexanecarboxylic acid, respectively. When cycloaddition reactions were conducted at 1mM substrate concentrations, cyclization of monomeric units occurred. At 2mM 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 0.23microM, 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.
Choi
Won Jun
WJ
Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, USA.
Shi
Zhen-Dan
ZD
Worthy
Karen M
KM
Bindu
Lakshman
L
Karki
Rajeshri G
RG
Nicklaus
Marc C
MC
Fisher
Robert J
RJ
Burke
Terrence R
TR
D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D051380:GRB2 Adaptor Protein / Q000737:chemistry* / Q000187:drug effects; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry; D018909:src Homology Domains / Q000187:drug effects
D000480:Alkynes; D001386:Azides; D051380:GRB2 Adaptor Protein; D008024:Ligands; D047028:Macrocyclic Compounds; D014230:Triazoles; D003300:Copper