Synthesis of a 5-methylindolyl-containing macrocycle that displays ultrapotent Grb2 SH2 domain-binding affinity.
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. Here, a ring-closing metathesis approach is utilized to synthesize a 5-methylindolyl-containing tetrapeptide mimetic (6) that exhibits unprecedented in vitro Grb2 SH2 domain-binding affinity (K(d) = 93 pM). Key to the preparation of 6 is the enantioselective synthesis of (2S)-2-(3-(5-methylindolyl)methyl)pent-4-enylamine (12) as one of two ring-closing segments.
Shi
Zhen-Dan
ZD
Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Lee
Kyeong
K
Wei
Chang-Qing
CQ
Roberts
Lindsey R
LR
Worthy
Karen M
KM
Fisher
Robert J
RJ
Burke
Terrence R
TR
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003500:Cyclization; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D018909:src Homology Domains
D000970:Antineoplastic Agents; D007211:Indoles; D009842:Oligopeptides