Exocyclic Control of Turn Induction in Macrocyclic Peptide Scaffolds

Zaretsky, Serge; Scully, Conor C. G.; Lough, Alan J.; Yudin, Andrei K.

doi:10.1002/chem.201303453

Cited by 58 publications

(52 citation statements)

References 42 publications

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“…X-ray crystallography is another valuable tool in the conformational analysis of macrocycles, although caution is advised with regard to the relevance of this analysis as solvent-dependent behavior in solution can lead to completely different conclusions. 60 Circular dichroism can be indispensable in the studies of protein secondary structure fragments embedded in macrocycles. Here too, one has to be aware of the danger to over-interpret the data.…”

Section: Properties Of Macrocyclesmentioning

confidence: 99%

Macrocycles: lessons from the distant past, recent developments, and future directions

2015

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Section: Properties Of Macrocyclesmentioning

confidence: 99%

Macrocycles: lessons from the distant past, recent developments, and future directions

2015

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“…This observation was rationalised by Zaretsky et al., who demonstrated in solution that a stereochemistry match between the aziridine aldehyde dimer and amino acid partners was paramount to obtaining good diastereoselectivity in the disrupted Ugi reaction with secondary amino acids 16. For previous discussion on the importance of a terminal Pro residue, see references 5, 14, 16; for the use of alternative isocyanides, see references 6f, 16.…”

Section: Resultsmentioning

confidence: 96%

“…h The rationale behind this efficiency has been provisionally attributed to the maintenance, through each intermediate step, of a stabilising ion pair that facilitates chain folding and keeps the two ends in close proximity 6d. The resulting endocyclic aziridine amide can be opened post‐macrocyclisation with a variety of nucleophiles, which adds an extra point of diversity to introduce exocyclic substituents 6a,f. 7…”

Section: Introductionmentioning

confidence: 99%

Solid‐Phase Parallel Synthesis of Functionalised Medium‐to‐Large Cyclic Peptidomimetics through Three‐Component Coupling Driven by Aziridine Aldehyde Dimers

Treder

Hickey

Tremblay

et al. 2015

Chemistry A European J

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The first solid-phase parallel synthesis of macrocyclic peptides using three-component coupling driven by aziridine aldehyde dimers is described. The method supports the synthesis of 9- to 18-membered aziridine-containing macrocycles, which are then functionalized by nucleophilic opening of the aziridine ring. This constitutes a robust approach for the rapid parallel synthesis of macrocyclic peptides.

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“…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.

233

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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Exocyclic Control of Turn Induction in Macrocyclic Peptide Scaffolds

Cited by 58 publications

References 42 publications

Macrocycles: lessons from the distant past, recent developments, and future directions

Macrocycles: lessons from the distant past, recent developments, and future directions

Solid‐Phase Parallel Synthesis of Functionalised Medium‐to‐Large Cyclic Peptidomimetics through Three‐Component Coupling Driven by Aziridine Aldehyde Dimers

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

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