Advancing Multicomponent Strategies to Macrobicyclic Peptides.

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected ß-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.

Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling.

In the past decade, multicomponent reactions have experienced a renaissance as powerful peptide macrocyclization tools enabling the rapid creation of skeletal complexity and diversity with low synthetic cost. This review provides both a historical and modern overview of the development of the peptide multicomponent macrocyclization as a strategy capable to compete with the classic peptide cyclization methods in terms of chemical efficiency and synthetic scope. We prove that the utilization of multicomponent reactions for cyclizing peptides by either their termini or side chains provides a key advantage over those more established methods; that is, the possibility to explore the cyclic peptide chemotype space not only at the amino acid sequence but also at the ring-forming moiety. Owing to its multicomponent nature, this type of peptide cyclization process is well-suited to generate diversity at both the endo- and exo-cyclic fragments formed during the ring-closing step, which stands as a distinctive and useful characteristic for the creation and screening of cyclic peptide libraries. Examples of the novel multicomponent peptide stapling approach and heterocycle ring-forming macrocyclizations are included, along with multicomponent methods incorporating macrocyclization handles and the one-pot syntheses of macromulticyclic peptide cages. Interesting applications of this strategy in the field of drug discovery and chemical biology are provided.

Peptide macrocyclization by transition metal catalysis.

Peptide macrocyclization has traditionally relied on lactam, lactone and disulfide bond-forming reactions that aim at introducing conformational constraints into small peptide sequences. With the advent of ruthenium-catalyzed ring-closing metathesis and copper-catalyzed alkyne-azide cycloaddition, peptide chemists embraced transition metal catalysis as a powerful macrocyclization tool with relevant applications in chemical biological and peptide drug discovery. This article provides a comprehensive overview of the reactivity and methodological diversification of metal-catalyzed peptide macrocyclization as a special class of late-stage peptide derivatization method. We report the evolution from classic palladium-catalyzed cross-coupling approaches to more modern oxidative versions based on C-H activation, heteroatom alkylation/arylation and annulation processes, in which aspects such as chemoselectivity and diversity generation at the ring-closing moiety became dominant over the last years. The transit from early cycloadditions and alkyne couplings as ring-closing steps to very recent 3d metal-catalyzed macrocyclization methods is highlighted. Similarly, the new trends in decarboxylative radical macrocyclizations and the interplay between photoredox and transition metal catalysis are included. This review charts future perspectives in the field hoping to encourage further progress and applications, while bringing attention to the countless possibilities available by diversifying not only the metal, but also the reactivity modes and tactics to bring peptide functional groups together and produce structurally diverse macrocycles.

Multicomponent Reactions in Ligation and Bioconjugation Chemistry.

Multicomponent reactions (MCRs) encompass an exciting class of chemical transformations that have proven success in almost all fields of synthetic organic chemistry. These convergent procedures incorporate three or more reactants into a final product in one pot, thus combining high levels of complexity and diversity generation with low synthetic cost. Striking applications of these processes are found in heterocycle, peptidomimetic, and natural product syntheses. However, their potential in the preparation of large macro- and biomolecular constructs has been realized just recently. This Account describes the most relevant results of our group in the utilization of MCRs for ligation/conjugation of biomolecules along with significant contributions from other laboratories that validate the utility of this special class of bioconjugation process. Thus, MCRs have proven to be efficient in the ligation of lipids to peptides and oligosaccharides as well as the ligation of steroids, carbohydrates, and fluorescent and affinity tags to peptides and proteins. In the field of glycolipids, we highlight the power of isocyanide-based MCRs with the one-pot double lipidation of glycan fragments functionalized as either the carboxylic acid or amine. In peptide chemistry, the versatility of the multicomponent ligation strategy is demonstrated in both solution-phase lipidation protocols and solid-phase procedures enabling the simultaneous lipidation and biotinylation of peptides. In addition, we show that MCRs are powerful methods for synchronized lipidation/labeling and macrocyclization of peptides, thus accomplishing in one step what usually requires long sequences. In the realm of protein bioconjugation, MCRs have also proven to be effective in labeling, site-selective modification, immobilization, and glycoconjugation processes. For example, we illustrate a successful application of multicomponent polysaccharide-protein conjugation with the preparation of multivalent glycoconjugate vaccine candidates by the ligation of two antigenic capsular polysaccharides of a pathogenic bacterium to carrier proteins. By highlighting the ability to join several biomolecules in only one synthetic operation, we hope to encourage the biomolecular chemistry community to apply this powerful chemistry to novel biomedicinal challenges.

Steroid diversification by multicomponent reactions.

Reports on structural diversification of steroids by means of multicomponent reactions (MCRs) have significantly increased over the last decade. This review covers the most relevant strategies dealing with the use of steroidal substrates in MCRs, including the synthesis of steroidal heterocycles and macrocycles as well as the conjugation of steroids to amino acids, peptides and carbohydrates. We demonstrate that steroids are available with almost all types of MCR reactive functionalities, e.g., carbonyl, carboxylic acid, alkyne, amine, isocyanide, boronic acid, etc., and that steroids are suitable starting materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and supramolecular chemistry applications.

On the CN-K coordination modes in Kn[M6-n(CN)6]·xH2O: first evidence of CN-K electron-deficient bonding.

Based on the determination of single crystal XRD structures of potassium hexacyanidometallates and on IR, and Raman data, here we propose for the first time the occurrence of an electron-deficient bonding between the N end of the CN- ligand and the K+ metal center. The crystal structures of Kn[M6-n(CN)6]·xH2O (M = Fe(ii), Ru(ii), Os(ii), Co(iii), Rh(iii), Ir(iii), Pt(iv)) reveal the presence of four types of CN-K interactions: (i) a linear CN-K bond, (ii) the N ends in a bipodal coordination involving two K atoms, (iii) the N ends in a tripodal coordination mode involving three K atoms and (iv) the N ends and the K atoms with the largest K-N distances within the subseries that can be attributed to the electrostatic interactions. The bi- and tripodal coordination modes between the N end of the CN- ligand and K+ ions are atypical and their nature is discussed in this contribution. The CN- ligand N end can behave as a two-electron donor that participates in a three-center two-electron bonding (i.e. Class II µ-L 3c-2e) for a N-bipodal coordination mode or as a two-electron donor that participates in a four-center two-electron bonding (4c-2e) for an N-tripodal coordination mode. Such a possibility is closely related to the π-back donation ability of the CN- ligand, which results in a charge density accumulation on the N end, which could be partially donated to the K atom through an σ-mechanism. For the divalent metals (Fe, Ru, Os), the solids crystallize with a monoclinic unit cell in the C2/c space group, while for the trivalent ones (Co, Rh, Ir), the crystal structure corresponds to an orthorhombic unit cell in the Pbcn space group. Potassium hexacyanidoplatinate(iv) crystallizes with a trigonal unit cell, in the P3[combining macron]1m space group, where each N end is always found coordinating two K atoms. The finding of these novel coordination modes of the CN- ligands, relying on an electron-deficient bonding behavior, paves the way for the design of functional materials based on hexacyanidometallates. The experimental results and the proposed electron-deficient bonding model herein discussed were appropriately supported by the computational calculations.

Macrocyclic Iminopeptides Diversify To Better Target Proteins.

Among the many methods available for accessing conformationally diverse cyclic peptides, the derivatization of macrocyclic iminopeptides has remained notably underexplored. Now, a relevant complexity-generating method expands the repertoire of synthetic strategies exploiting the reactivity of an imino bond embedded in the cyclic peptide skeleton. Here we highlight a recent report describing the on-resin construction of a new family of macrocyclic peptide/natural product-inspired hybrids, namely "PepNats", by derivatization of cyclic iminopeptides through 1,3-cycloaddition reactions. A proof-of-concept with PepNats bearing peptide sequences that mimic protein hot loops demonstrated the potential of this strategy to create novel macrocyclic peptide ligands capable of modulating protein-protein interactions.

CuICuII and AgIp-isocyanobenzoates as novel 1D semiconducting coordination oligomers.

Two novel semiconducting coordination oligomers with 1D chain structures, namely [H0.07 CuI0.65CuII0.14(µ-p-CNC6H4CO2)·0.9H2O]n and [Ag(µ-p-CNC6H4CO2)]n, were obtained and characterized by XRD powder patterns, and XPS, EPR, UV-vis-NIR, IR and Raman spectroscopy. According to XRD analysis, CuICuII-ICNBA is an amorphous solid, while AgI-ICNBA crystalizes with a monoclinic unit cell in the C2/c space group (Z = 4). The composition and further information of CuICuII-ICNBA were obtained from the spectroscopic data. In correspondence with the quantification of terminal groups from high-resolution XPS spectra, CuICuII-ICNBA and AgI-ICNBA are composed of an average of 9 and 7 monomer units, respectively, resulting in 1D-oligomers. The spectroscopic evidence indicates that CuICuII-ICNBA is better described as a non-stoichiometric coordination oligomer (where non-integer ratios of metal ions can be accommodated), while AgI-ICNBA is stoichiometric. In both materials, each metal center is linked by two µ-η1:η1-p-isocyanobenzoate ligands forming microfibers of around 120 nm (CuICuII-material) and 310 nm (AgI-material) in average diameters with optical band gaps of 2.60 eV and 2.17 eV, respectively.