Structural Basis for α-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization.

In situ generation of zinc carbenoids from diazo compounds and zinc salts: asymmetric synthesis of 1,2,3-substituted cyclopropanes.

The first enantioselective cyclopropanation of alkenes using zinc carbenoids generated in situ from diazo compounds and zinc salts is reported. This new method allows the highly enantio- and diastereoselective synthesis of 1,2,3-substituted cyclopropanes via aryl-substituted carbenoids. The first Simmons-Smith reaction using a catalytic amount of zinc to generate enantioenriched cyclopropane is also reported.

General method for the synthesis of phenyliodonium ylides from malonate esters: easy access to 1,1-cyclopropane diesters.

A general method to access phenyliodonium ylides from malonates has been developed. These ylides provide easy access to a variety of useful 1,1-cyclopropane diesters using rhodium or copper catalysis. Moreover, the iodonium ylide of dimethyl malonate was obtained in 78% yield using improved conditions that involve a simple filtration step to isolate the desired product. This ylide was shown to be a safer and convenient alternative to the corresponding diazo compound and a very efficient way to 1,1-cyclopropane diesters when used with a catalytic amount of Rh(2)(esp)(2).

trans-Directing ability of the amide group: enabling the enantiocontrol in the synthesis of 1,1-dicarboxy cyclopropanes. Reaction development, scope, and synthetic applications.

In this article, we describe our efforts toward the enantioselective formation of 1,1-cyclopropane diesters via the metal-catalyzed cyclopropanation of olefins. The strategies envisioned to achieve such a goal are discussed as well as the results that led us to the discovery of the powerful trans-directing ability of the amide group in Rh(II)-catalyzed cyclopropanation reactions. We show how this feature enables a solution for the stereoselective synthesis of 1,1-dicarboxy cyclopropane derivatives. The scope and limitations are discussed as well as the demonstration that these newly formed cyclopropanes display reactivity similar to that of 1,1-cyclopropane diesters. Conversely, 1,1-cyclopropane diesters could be accessed in two steps from commercially available alkenes. The potential utility of this methodology is illustrated by several functional group transformations and its use in the expedient stereoselective formal synthesis of (S)-(+)-curcumene, (S)-(+)-nuciferal, (S)-(+)-nuciferol, (+)-erogorgiaene, (+/-)-xanthorrhizol, and (+/-)-2-hydroxycalamenene.

Peptide-oligourea hybrids analogue of GLP-1 with improved action in vivo.

Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.

Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking.

The high demand of the pharmaceutical industry for new modalities to address the diversification of biological targets with large surfaces of interaction led us to investigate the replacement of α-amino acid residues with ureido units at selected positions in peptides to improve potency and generate effective incretin mimics. Based on molecular dynamics simulations, N-terminally modified GLP-1 analogues with a ureido residue replacement at position 2 were synthesized and showed preservation of agonist activity while exhibiting a substantial increase in stability. This enabling platform was applied to exenatide and lixisenatide analogues to generate two new ureidopeptides with antidiabetic properties and longer duration of action. Further analyses demonstrated that the improvement was due mainly to differences in signal bias and trafficking of the GLP-1 receptor. This study demonstrates the efficacy of single α-amino acid substitution with ureido residues to design long lasting peptides.

Cycloadditions of aromatic azomethine imines with 1,1-cyclopropane diesters.

The cycloaddition of aromatic azomethine imines to 1,1-cyclopropane diesters was achieved using Ni(ClO4)2 as catalyst. The methodology gives access to unique tricyclic dihydroquinoline derivatives with dr up to 6.6:1. A nonconcerted mechanism is proposed on the basis of stereochemical analysis of the reaction.

Improved zinc-catalyzed Simmons-Smith reaction: access to various 1,2,3-trisubstituted cyclopropanes.

The Simmons-Smith reaction of zinc carbenoids with alkenes is a powerful method to access cyclopropanes containing various substitution patterns. This work exploits the high reactivity of aryldiazomethanes toward zinc halides to generate aryl-substituted carbenoids catalytically. These carbenoids are able to cyclopropanate various alkenes diastereoselectively, including unfunctionalized substrates such as styrenes. The zinc catalyst can be modified to tolerate the use of free allylic alcohols.

Synthesis of enantioenriched allenes from 1,1-cyclopropanediesters.

Highly substituted allenes were obtained by the S(N)2' addition of organocuprate reagents on 2-propargyl-1,1-cyclopropanediesters. This new methodology permits the synthesis of highly enantioenriched allenes as the reaction proceeds with retention of the enantiomeric purity of the starting cyclopropane. The use of higher order cuprates was instrumental in obtaining the reported results.