Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis.
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.
Liu
Fa
F
Laboratory of Medicinal Chemistry, Bldg. 376 Boyles St., Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Worthy
Karen M
KM
Bindu
Lakshman
L
Giubellino
Alessio
A
Bottaro
Donald P
DP
Fisher
Robert J
RJ
Burke
Terrence R
TR
D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry; D000818:Animals; D002625:Chemistry, Organic / Q000379:methods*; D066246:ErbB Receptors / Q000737:chemistry*; D051380:GRB2 Adaptor Protein / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D019000:Phosphotyrosine; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D018909:src Homology Domains
D000577:Amides; D000588:Amines; D051380:GRB2 Adaptor Protein; D010455:Peptides; D019000:Phosphotyrosine; D066246:ErbB Receptors