Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics

Abstract

Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl-and allyl-functionality appended to the β-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure, may facilitate the development of therapeutically-relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.

Structural and Pharmacological Effects of Ring-Closing Metathesis in Peptides

“…These protein domains primarily recognize sequences of the type pTyr-Xaa 1 -Asn-Xaa 2 in type-I β-turns. Burke and co-workers utilized RCM to prepare a series of macrocyclic analogues 56 of the low micromolar (K D = 5.6 μM) Grb SH2 domain-binding ligand 57 ( Figure 15 ) with varying bridge lengths (m = 3 or 4), positioning and stereochemistry of the resulting double bond and stereochemistry at the bridgeheads [ 72 , 73 , 74 ]. Formally, these cyclizations could be classified as N( i )→C α ( i+2 ) cyclizations, but the close similarity between the N-terminal part of 57 and a substituted aspartic acid residue makes it more natural to classify them as “N”( i )→C α ( i+3 ) cyclizations.…”

Metathesis in Peptides and Peptidomimetics

“…[57] Recently, RCM was also applied for the synthesis of 15-membered macrocycles as Grb SH2 domain binding tetrapeptide mimetics with low nanomolar affinities. [58] Similarly, a novel cyclic peptide MC4-ligand was achieved by RCM. [59] Interestingly, in the case of the antimicrobial leucocin polypeptide, the acyclic diallyl-leucocin was one order of magnitude more active than the dicarba analogue obtained by RCM.…”