Solid-Supported Synthesis of Putative Peptide β-Turn Mimetics via Ugi Reaction for Diketopiperazine Formation

Gołębiowski, Adam; Jóźwik, Julita; Klopfenstein, Sean R.; Colson, Anny‐Odile; Grieb, Arthur L; Russell, Anne F.; Rastogi, Vinit L; Diven, Conrad; Portlock, David E.; Chen, Jack J.

doi:10.1021/cc020029u

Cited by 54 publications

(40 citation statements)

References 26 publications

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“…Examples are bicyclic scaffolds such as diketopiperazines. A multicomponent approach to these latter scaffolds is described by Golebiowski et al (Scheme 60) [156,160]. Herein, the Ugi reaction involving resin-bound amine 198 and an excess of R -(+)-2-bromoalkyl acid 199 , isocyanide and aldehyde (5 equiv) afforded the linear dipeptide 200 that after acidic Boc-removal and base-catalyzed S n 2-cyclization was converted to the monocyclic ketopiperazine 201 .…”

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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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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“…9) share the same diketopiperazine framework [27,[29][30][31]36], a well known privileged substructure, [83] and match loop clusters closely. SciFinder show there are 22 synthesized derivatives, however all the associated references do not report any assay for biological activities for the specific bicyclic diketopiperazine scaffold, and therefore, no conclusions can be drawn from these three b-turn mimetics templates.…”

Section: Biologically Relevant Descriptorsmentioning

confidence: 99%

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.

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“…With the aim of preparing bicyclic diketopiperazines as potential b-turn mimetics [351], a-N-Boc-b-N-Fmoc-optically active diaminopropionic acids were attached to a standard Merrifield's hydroxymethyl resin under Mitsunobu conditions to afford [428]. Fmoc deprotection and subsequent Ugi reaction using, as the carboxylic component, optically active 2-bromoalkyl acids (430), afforded the required intermediates (431).…”

Section: Ugi Reaction With Solid-supported Aminesmentioning

confidence: 99%

CC Bond‐Forming Reactions

Brill¹,

Papeo²

2006

Combinatorial Chemistry

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Solid-Supported Synthesis of Putative Peptide β-Turn Mimetics via Ugi Reaction for Diketopiperazine Formation

Cited by 54 publications

References 26 publications

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

CC Bond‐Forming Reactions

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