Choi Won Jun, Shi Zhen-Dan, Worthy Karen M, Bindu Lakshman, Karki Rajeshri G, Nicklaus Marc C, Fisher Robert J, Burke Terrence R
Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, USA.
Bioorg Med Chem Lett. 2006 Oct 15;16(20):5265-9. doi: 10.1016/j.bmcl.2006.08.004.
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.
铜（I）促进的叠氮化物与末端炔烃的[3+2]休斯根环加成反应被用于基于Grb2 SH2结构域结合基序“Pmp-Ac(6)c-Asn”制备含三唑的大环化合物，其中Pmp和Ac(6)c分别代表4-膦酰甲基苯丙氨酸和1-氨基环己烷羧酸。当环加成反应在1mM底物浓度下进行时，单体单元发生环化。在2mM底物浓度下，主要产物是大环二聚体。在Grb2 SH2结构域结合测定中，含单体（S）-Pmp的大环化合物的解离常数（K(d)）值为0.23微摩尔，而相应的二聚体大环化合物的亲和力则高出50倍以上。还发现开链二聚体具有与二聚体大环化合物相同的亲和力。这项工作代表了“点击化学”在SH2结构域结合抑制剂合成中的首次应用，并表明了其潜在用途。
