Article

Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis.

Laboratory of Medicinal Chemistry, Bldg. 376 Boyles St., Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Organic & Biomolecular Chemistry (impact factor: 3.7). 02/2007; 5(2):367-72. DOI:10.1039/b611887a pp.367-72
Source: PubMed

ABSTRACT 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 (K(D) = 1.3 nM) that was nearly equal to the parent macrocycle (2), which bore a stereoselectively-introduced naphthylmethyl substituent at the upper ring junction (K(D) = 0.9 nM). The results of this study advance design considerations that should facilitate the development of Grb2 SH2 domain-binding antagonists.

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    Rebecca L Rich, David G Myszka
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Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

achiral 4-pentenylamides
 
bear bicyclic aryl substituents
 
cyclic constructs
 
cyclohexyl group
 
exhibit potent Grb2 SH2 domain-binding affinity
 
exhibited Grb2 SH2 domain-binding affinity
 
Grb2 SH2 domain-binding affinities
 
Grb2 SH2 domain-binding antagonists
 
higher affinities
 
macrocycles
 
macrocycles presents
 
macrocycles varied
 
parent macrocycle
 
potential limit
 
ring-closing metathesis
 
stereoselectively-introduced naphthylmethyl substituent
 
stereoselectively-introduced upper ring junctions
 
study advance design considerations
 
therapeutic application
 
upper ring junction