Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived <i>N</i>-Alkylated Peptides: The Quest for Functionalized β-Turns

Ricardo, Manuel G.; Vasco, Aldrin V.; Rivera, Daniel G.; Wessjohann, Ludger A.

doi:10.1021/acs.orglett.9b02592

Cited by 15 publications

(7 citation statements)

References 20 publications

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“…Multicomponent reactions, which are procedures incorporating three or more reactants into a final product in one pot, have been very useful for the synthesis of peptidomimetics, [14] including cyclic ones with β‐turn conformations [15] . We have also developed Ugi multicomponent macrocyclization methods to assemble macrocyclic peptides having α‐helix [16] and β‐hairpin [17] secondary structures. When aiming at producing Ugi‐analogs of octreotide, three crucial issues should be considered.…”

Section: Resultsmentioning

confidence: 99%

Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

et al. 2022

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The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an on-resin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.

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Section: Resultsmentioning

confidence: 99%

Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

et al. 2022

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“…Solid-supported Ugi-4-component macrocyclization methodology was subsequently reported to synthesize polycationic cyclolipopeptides with stabilized helical structures and antimicrobial properties [ 146 ], short and medium-size canonical cyclopeptides with turn-inducing moieties [ 147 ], stabilized cyclic β-hairpins, and N -alkylated peptides with various exo-cyclic functionalization such as cationic or hydrophobic tails and bioconjugation handles to install fluorescent and affinity tags, etc. [ 148 ]. In 2019, Reguera and Rivera reviewed the applications of the MCR toolbox for peptide macrocyclization and stapling [ 149 ].…”

Section: Microwave-assisted And/or Solid-supported Synthesis Of Macro...mentioning

confidence: 99%

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Sun

2022

Molecules

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Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

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“…The synthesis of various cyclopeptide backbone and structurally similar crassipin B were prepared on solid phase with the use of Rink amide resins [37] . Two years later, the on‐resin Ugi reactions were improved by the same group, which further implemented the construction of N ‐alkylated dipeptide fragments that aligned antiparallel β‐sheets in a macrocyclic scaffold of β‐hairpin templates [38] …”

Section: Diverse Synthetic Approaches To the Macrocycles In Cyclopeptmentioning

confidence: 99%

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

Wang

Joullié

2021

The Chemical Record

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The cyclopeptide alkaloids are cyclic depsipeptides incorporating cyclophanes with polyamide units 13‐, 14‐ and 15‐membered macrocyclic systems. Although various pharmacological activities have been ascribed to cyclopeptide alkaloids from plants of the Rhamnacea family, these studies have been hampered by their low availability due to the lack of reasonable amounts distributed in nature. Therefore, novel and efficient synthetic approaches should be an important aim, which inspired us to examine how to diversely construct the unique structures of this type of natural products. In this account, several typical strategies are presented in terms of efficient, stereocontrolled and regioselective synthesis of cyclopeptide alkaloids.

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Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns

Cited by 15 publications

References 20 publications

Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

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