High Throughput Solid Phase Parallel Synthesis of Macrocyclic Peptidomimetics

Marsault, Éric; Hoveyda, Hamid R.; Peterson, Mark L.; Gagnon, René; Vézina, Martin; Pinault, Jean François; Landry, Annick; Saint-Louis, Carl Jacky; Ouellet, Luc; Beauchemin, Sophie; Benakli, Kamel; Beaubien, Sylvie; Brassard, Martin; Wang, Z.; Champagne, Manon; Galaud, Fabrice; Fortin, Nadia; Fortin, Daniel; Plourde, V.; Ramaseshan, Mahesh; Bhat, Shridhar; Bilodeau, François; Lonergan, David; Lan, Ruoxi; Li, S.; Berthiaume, Gilles; Foucher, Laurence; Peng, Xiaowen; Dory, Yves L.; Deslongchamps, Pierre

doi:10.1007/978-0-387-73657-0_7

Cited by 7 publications

(4 citation statements)

References 8 publications

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“…352,353 Noteworthy aspects of the solid phase process, which yielded a screening library of over 40,000 diverse compounds (general structure 269, Figure 11.19, site of cyclization and reagent employed indicated), were (a) the use of a thioester linker that enabled cyclization to form the macrolactam to occur simultaneous with cleavage from the resin (''cyclization-release'' as described in Section 11.2), 54 (b) the formation of the C-N sp 3 bond between the amino acid chain and the tether utilized an N-benzothiazole-2-sulphonyl (Bts) 354 moiety for dual roles, first as protection of the amine and then for activation towards use in a Fukuyama-Mitsunobu reaction, and (c) the optional addition of silver to assist with difficult cyclizations. 355 Compounds of this type were also accessed using RCM.…”

Section: Synthesis At Scalementioning

confidence: 98%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Section: Synthesis At Scalementioning

confidence: 98%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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“…Yet another area of Éric’s work was the permeability of macrocycles and guanidine-rich transporters with a twin focus on (1) understanding the structure–permeability and structure–property relationships of semipeptidic macrocycles and (2) modulating guanidine-rich transporter structure to gain better insight into cellular-membrane chemistry and to help design selective agents to shuttle cargo into cells (Figure ). − Éric coauthored several reviews on the impact of macrocycles in drug discovery and was a guest editor of Practical Medicinal Chemistry with Macrocycles . − …”

Section: A Medicinal Chemist Pioneering Macrocyclic Researchmentioning

confidence: 99%

Éric Marsault (1971–2021): A Legacy through the Prism of Relationship Chemistry

Sarret

2021

J. Med. Chem.

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“…However, a conventional peptoid synthesizer based on a peptide synthesizer does not allow for the synthesis of large split and mix libraries. The IRORI technology is a commercially available format of nano- up to macro-reactors that allows for maximizing the benefits of split and mix synthesis while enabling the automated production of larger amounts of single compounds per reactor [30,31,32,33,34,35,36] (Figure 1). This technology supports the synthesis of large and chemically diverse libraries by the use of directed sorting technology based on glass coated radiofrequency (Rf) tags embedded in the reactors.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we established the submonomer-based solid phase synthesis of a “proof of principle” CPPo library in IRORI MiniKans [31,32,33,34,35,36]. Eventually, the CPPo library was applied to HeLa cells for the screening of organelle targeting CPPos.…”

Section: Introductionmentioning

confidence: 99%

Cell Penetrating Peptoids (CPPos): Synthesis of a Small Combinatorial Library by Using IRORI MiniKans

et al. 2012

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Cell penetrating peptoids (CPPos) are potent mimics of the corresponding cell penetrating peptides (CPPs). The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a “proof of principle” peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines)] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached.

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High Throughput Solid Phase Parallel Synthesis of Macrocyclic Peptidomimetics

Cited by 7 publications

References 8 publications

The Synthesis of Macrocycles for Drug Discovery

The Synthesis of Macrocycles for Drug Discovery

Éric Marsault (1971–2021): A Legacy through the Prism of Relationship Chemistry

Cell Penetrating Peptoids (CPPos): Synthesis of a Small Combinatorial Library by Using IRORI MiniKans

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