Abstract
In 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.
Highlights
Peptides and proteins fulfill a key role in many biological and physiological functions of living organisms
Natural peptides often occur in an ensemble of conformations thereby reducing their specificity for biological targets resulting in unwanted side effects [3,4]
These isocyanidebased multicomponent reactions (IMCRs) provide linear products, whereas their cyclic analogues are highly desirable as discussed above for potentially improved structural and biological properties. These linear products can be cyclized via post-condensation transformations since a wide range of unreactive functional groups are tolerated in the IMCRs [19]. In this overview we focus on all recent developments in the last decade in the field of cyclic peptidomimetics obtained from IMCRs and their subsequent cyclization reactions
Summary
Peptides and proteins fulfill a key role in many biological and physiological functions of living organisms. In the context of design and synthesis of peptidomimetics, several approaches have been applied and most of them include a sequence of multiple reactions along with a variety of protection and deprotection steps Via these rather long sequential procedures it is often not straightforward to introduce structural diversity in a set of targeted peptide mimics, which is essential for effective fine tuning of biological activity [11,12,13]. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs), such as the Ugi and the Passerini reaction, are the most relevant reactions for constructing peptidomimetics since they give access to (depsi)peptide-like structures These IMCRs provide linear products, whereas their cyclic analogues are highly desirable as discussed above for potentially improved structural and biological properties. Cyclic peptidomimetics can be obtained via subsequent transformations that in turn are possible via e.g. the incorporation of bifunctional substrates or by activation of functionalized substrates in the initial MCR [19]
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