Development of bombesin-tubulysin conjugates using multicomponent chemistry to functionalize both the payload and the homing peptide.

Peptide-drug conjugates (PDCs) have recently gained significant attention for the targeted delivery of anticancer therapeutics, mainly due to their cost-effective and chemically defined production and lower antigenicity compared to ADCs, among other benefits. In this study, we designed and synthesized novel PDCs by conjugating new thiol-functionalized tubulysin analogs (tubugis) to bombesin, a peptide ligand with a relevant role in cancer research. Two tubulysin analogs bearing ready-for-conjugation thiol groups were prepared by an on-resin multicomponent peptide synthesis strategy and subsequently tested for their stand-alone anti-proliferative activity against human cancer cells, which resulted in IC values in the nanomolar range.

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.

On the CNK coordination modes in K[M(CN)]·xHO: first evidence of CNK 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 K[M(CN)]·xHO (M = Fe(ii), Ru(ii), Os(ii), Co(iii), Rh(iii), Ir(iii), Pt(iv)) reveal the presence of four types of CNK 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.

CuCu and Ag-isocyanobenzoates as novel 1D semiconducting coordination oligomers.

Two novel semiconducting coordination oligomers with 1D chain structures, namely [H0.07 CuI0.65CuII0.

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.

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.

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.

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.

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.