882301-73-7Relevant academic research and scientific papers
Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis
Liu, Fa,Worthy, Karen M.,Bindu, Lakshman,Giubellino, Alessio,Bottaro, Donald P.,Fisher, Robert J.,Burke Jr., Terrence R.
, p. 367 - 372 (2007)
A family of previously reported ring-closing metathesis (RCM)-derived macrocycles that exhibit potent Grb2 SH2 domain-binding affinity is characterized by stereoselectively-introduced upper ring junctions that bear bicyclic aryl substituents. However, the synthetic complexity of these macrocycles presents a potential limit to their therapeutic application. Therefore, the current study was undertaken to simplify these macrocycles through the use of achiral 4-pentenylamides as ring-forming components. A series of macrocycles (5a-f) was prepared bearing both open and cyclic constructs at the upper ring junction. The Grb2 SH2 domain-binding affinities of these macrocycles varied, with higher affinities being obtained with cyclo-substituents. The most potent analogue (5d) contained a cyclohexyl group and exhibited Grb2 SH2 domain-binding affinity (KD = 1.3 nM) that was nearly equal to the parent macrocycle (2), which bore a stereoselectively- introduced naphthylmethyl substituent at the upper ring junction (KD = 0.9 nM). The results of this study advance design considerations that should facilitate the development of Grb2 SH2 domain-binding antagonists. This journal is The Royal Society of Chemistry.
MACROCYCLIC SH2 DOMAIN BINDING INHIBITORS
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Page/Page column 25, (2010/10/20)
Disclosed are compounds for inhibiting the binding of an SH2 domain-containing protein, for example, a compound of formula (I): FORMULA (I) wherein R1 is a lipophile; R2, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected
