Solvatochromic Reagents for Multicomponent Reactions and their Utility in the Development of Cell‐Permeable Macrocyclic Peptide Vectors

Rotstein, Benjamin H.; Mourtada, Rida; Kelley, Shana O.; Yudin, Andrei K.

doi:10.1002/chem.201102096

Cited by 38 publications

(34 citation statements)

References 75 publications

(13 reference statements)

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“…[47,48] Subsequent methylation in neat methyl iodide and workup provided analytically pure salt 1H. The first step consisted of simple bromine displacement by treatment of 4-bromo-N-butyl-1,8-naphthal-imide with an excess amount of imidazole and base in polar solvent with heating to afford 4-imidazolyl-N-butyl-1,8naphthalimide.…”

Section: Resultsmentioning

confidence: 99%

Deep‐Red Phosphorescent Iridium(III) Complexes with Chromophoric N‐Heterocyclic Carbene Ligands: Design, Photophysical Properties, and DFT Calculations

et al. 2016

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Section: Resultsmentioning

confidence: 99%

Deep‐Red Phosphorescent Iridium(III) Complexes with Chromophoric N‐Heterocyclic Carbene Ligands: Design, Photophysical Properties, and DFT Calculations

et al. 2016

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“…Lately, multicomponent reactions (MCRs) have evolved from versatile methods for the synthesis of small molecules to powerful tools for the post‐synthetic derivatization of peptides and proteins . Among the relevant multicomponent transformations recently conducted with peptides are cyclization, lipidation, and labeling . Thus far, there are several isocyanide MCRs available for the multicomponent cyclization of peptides, while the Strecker reaction and the metal‐catalyzed A 3 ‐coupling have been recently added to this repertoire.…”

Section: Methodsmentioning

confidence: 99%

Introducing the Petasis Reaction for Late‐Stage Multicomponent Diversification, Labeling, and Stapling of Peptides

et al. 2019

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For the first time, the Petasis (borono‐Mannich) reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid‐phase derivatization of peptides at the N‐terminus, Lys, and Nϵ‐MeLys side‐chains by an on‐resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid, and aldoses, thus encompassing a powerful complexity‐generating approach without changing the charge of the peptides. The multicomponent stapling was conducted in solution by linking Nϵ‐MeLys or Orn side‐chains, positioned at i, i+7 and i, i+4, with aryl tethers, while hydroxy carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology.

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“…The amphoteric aldehydes 348 in the Yudin macrocyclization strategy can be applied under conventional reactant conencentrations and overcomes both the stereoselectivity and oligomerization issues producing in good yields and excellent diastereoselectivities macrocyclic peptides 351 avoiding epimerization. In follow-up work a number of interesting applications were discussed [250] including the use of solvatochromic isocyanides 352 to access cell permeable macrocyclic peptide vectors [251] and RGD fluorescent probes [252]. In addition, the macrocyclization tool proved very useful in the exocyclic control over turn induction in macrocyclic petides [253].…”

Section: Reviewmentioning

confidence: 99%

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Koopmanschap¹,

Ruijter²,

Orru³

2014

Beilstein J. Org. Chem.

230

117

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SummaryIn the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR-components that bear an additional alkene, alkyne or azide moiety and can be cyclized via either a deprotection–cyclization strategy, a ring-closing metathesis, a 1,3-dipolar cycloaddition or even via a sequence of multiple multicomponent reactions. The sequential IMCR-cyclization reactions can afford small cyclic peptide mimics (ranging from four- to seven-membered rings), medium-sized cyclic constructs or peptidic macrocycles (>12 membered rings). This review describes the developments since 2002 of IMCRs-cyclization strategies towards a wide variety of small cyclic mimics, medium sized cyclic constructs and macrocyclic peptidomimetics.

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Solvatochromic Reagents for Multicomponent Reactions and their Utility in the Development of Cell‐Permeable Macrocyclic Peptide Vectors

Cited by 38 publications

References 75 publications

Deep‐Red Phosphorescent Iridium(III) Complexes with Chromophoric N‐Heterocyclic Carbene Ligands: Design, Photophysical Properties, and DFT Calculations

Deep‐Red Phosphorescent Iridium(III) Complexes with Chromophoric N‐Heterocyclic Carbene Ligands: Design, Photophysical Properties, and DFT Calculations

Introducing the Petasis Reaction for Late‐Stage Multicomponent Diversification, Labeling, and Stapling of Peptides

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

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