Organic Carbon Monoxide Prodrugs Activated by Endogenous Reactive Oxygen Species for Targeted Delivery.

Carbon monoxide (CO) has demonstrated therapeutic benefits in reactive oxygen species (ROS)-rich environments, such as inflammation and cancer. However, the targeted delivery of CO remains challenging, limiting its clinical application and necessitating the development of improved CO-prodrugs. Herein, we report a radical-activated, metal-free, CO-prodrug designed to address delivery limitations and avoid metal-associated toxicity.

Mechanistic Insights into Chloride-Dependent Uncaging Reaction of Propargyl and Allene-Protected Substrates by Pd-Complexes.

This study investigates the effect of chloride levels on the mode of action of palladium complexes for the activation of propargyl- and allene-protected fluorophores and chemotherapeutic drugs through uncaging reactions. Four Pd(II) complexes were synthesized and characterized using various spectroscopic techniques to confirm their structure and electronic properties. Kinetic studies and density functional theory calculations revealed that chloride ions in phosphate buffered saline (PBS) significantly enhance catalytic efficiency, particularly for allenyl-protected substrates compared to propargylic counterparts.

Gold(III)-Induced Amide Bond Cleavage In Vivo: A Dual Release Strategy via π-Acid Mediated Allyl Substitution.

Selective cleavage of amide bonds holds prominent significance by facilitating precise manipulation of biomolecules, with implications spanning from basic research to therapeutic interventions. However, achieving selective cleavage of amide bonds via mild synthetic chemistry routes poses a critical challenge. Here, we report a novel amide bond-cleavage reaction triggered by Na[AuCl] in mild aqueous conditions, where a crucial cyclization step leads to the formation of a 5-membered ring intermediate that rapidly hydrolyses to release the free amine in high yields.

Darobactin Substrate Engineering and Computation Show Radical Stability Governs Ether versus C-C Bond Formation.

The Gram-negative selective antibiotic darobactin A has attracted interest owing to its intriguing fused bicyclic structure and unique targeting of the outer membrane protein BamA. Darobactin, a ribosomally synthesized and post-translationally modified peptide (RiPP), is produced by a radical -adenosyl methionine (rSAM)-dependent enzyme (DarE) and contains one ether and one C-C cross-link. Herein, we analyze the substrate tolerance of DarE and describe an underlying catalytic principle of the enzyme.

Interplay of chloride levels and palladium(ii)-catalyzed -deallenylation bioorthogonal uncaging reactions.

The palladium-mediated uncaging reaction of allene substrates remains a promising yet often overlooked strategy in the realm of bioorthogonal chemistry. This method exhibits high kinetic rates, rivaling those of the widely employed allylic and propargylic protecting groups. In this study, we investigate into the mechanistic aspects of the C-O bond-cleavage deallenylation reaction, examining how chloride levels influence the kinetics when triggered by Pd(ii) complexes.

Benzylic Radical Stabilization Permits Ether Formation During Darobactin Biosynthesis.

The Gram-negative selective antibiotic darobactin A has attracted interest owing to its intriguing fused bicyclic structure and unique mode of action. Biosynthetic studies have revealed that darobactin is a ribosomally synthesized and post-translationally modified peptide (RiPP). During maturation, the darobactin precursor peptide (DarA) is modified by a radical -adenosyl methionine (rSAM)-dependent enzyme (DarE) to contain ether and C-C crosslinks.

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-Component Reaction into a Single Multicomponent Process.

Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe a novel multicomponent approach based on the combination of the isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction to generate pyrazole amide derivatives. The scope of the reaction as well as mechanistic insights governing the 4H-pyrazol-4-imine tautomerization are provided.

NMR Shows Why a Small Chemical Change Almost Abolishes the Antimicrobial Activity of Glycocin F.

Glycocin F (GccF), a ribosomally synthesized, post-translationally modified peptide secreted by KW30, rapidly inhibits the growth of susceptible bacteria at nanomolar concentrations. Previous studies have highlighted structural features important for its activity and have shown the absolute requirement for the Ser18 -linked GlcNAc on the eight-residue loop linking the two short helices of the (C-X6-C) structure. Here, we show that an ostensibly very small chemical modification to Ser18, the substitution of the C proton with a methyl group, reduces the antimicrobial activity of GccF 1000-fold (IC 1.

Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C-C Bond Cleavage Reactions.

The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C-O or C-N bonds, which limits the scope of drugs to only those that present amino or hydroxyl groups. Here, we report the decaging of an -quinone prodrug, a propargylated β-lapachone derivative, through a palladium-mediated C-C bond cleavage.

Synthesis of Fluorescent Lanthipeptide Cytolysin S Analogues by Late-Stage Sulfamidate Ring Opening.

Nucleophilic ring opening of cyclic sulfamidates derived from amino acids is a common strategy for the synthesis of lanthionine derivatives. In this work, we report the regio-, chemo-, and stereoselective intramolecular S-alkylation of a cysteine residue with -sulfonyl sulfamidates for the synthesis of cyclic lanthionine-containing peptides. The strategy involves the solid-phase synthesis of sulfamidate-containing peptides followed by late-stage intramolecular cyclization.

Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems.

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (BuSnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.

Conformationally Restricted β-Sheet Breaker Peptides Incorporating Cyclic α-Methylisoserine Sulfamidates.

Peptides containing variations of the β-amyloid hydrophobic core and five-membered sulfamidates derived from β-amino acid α-methylisoserine have been synthesized and fully characterized in the gas phase, solid state and in aqueous solution by a combination of experimental and computational techniques. The cyclic sulfamidate group effectively locks the secondary structure at the N-terminus of such hybrid peptides imposing a conformational restriction and stabilizing non-extended structures. This conformational bias, which is maintained in the gas phase, solid state and aqueous solution, is shown to be resistant to structure templating through assays of in vitro β-amyloid aggregation, acting as β-sheet breaker peptides with moderate activity.

Towards Enantiomerically Pure Unnatural α-Amino Acids via Photoredox Catalytic 1,4-Additions to a Chiral Dehydroalanine.

Chemo- and diastereoselective 1,4-conjugate additions of anionic and radical -nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. Of particular importance, radical carbon photolysis by a catalytic photoredox process using a simple method with a metal-free photocatalyst provides exceptional yields and selectivities at room temperature. Moreover, these 1,4-conjugate additions offer an excellent starting point for synthesizing enantiomerically pure carbon-β-substituted unnatural α-amino acids (UAAs), which could have a high potential for applications in chemical biology.

Stereoselective α-Deuteration of Serine, Cysteine, Selenocysteine, and 2,3-Diaminopropanoic Acid Derivatives.

Efficient methodologies for synthesizing enantiopure α-deuterated derivatives of serine, cysteine, selenocysteine, and 2,3-diaminopropanoic acid have been developed. H/D exchange was achieved by deprotonation of a chiral bicyclic serine equivalent followed by selective deuteration. Additionally, diastereoselective additions of thiols, selenols, and amines to a chiral bicyclic dehydroalanine in deuterated alcohols allowed site-selective deuteration at the Cα atom of cysteine, selenocysteine, and 2,3-diaminopropanoic acid derivatives.

Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.

Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol.

Synthesis of β-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates.

Chiral bicyclic -acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem ,-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters.

Platform for Orthogonal -Cysteine-Specific Protein Modification Enabled by Cyclopropenone Reagents.

Protein conjugates are valuable tools for studying biological processes or producing therapeutics, such as antibody-drug conjugates. Despite the development of several protein conjugation strategies in recent years, the ability to modify one specific amino acid residue on a protein in the presence of other reactive side chains remains a challenge. We show that monosubstituted cyclopropenone (CPO) reagents react selectively with the 1,2-aminothiol groups of N-terminal cysteine residues to give a stable 1,4-thiazepan-5-one linkage under mild, biocompatible conditions.

Single Mutation on Trastuzumab Modulates the Stability of Antibody-Drug Conjugates Built Using Acetal-Based Linkers and Thiol-Maleimide Chemistry.

Antibody-drug conjugates (ADCs) are a class of targeted therapeutics used to selectively kill cancer cells. It is important that they remain intact in the bloodstream and release their payload in the target cancer cell for maximum efficacy and minimum toxicity. The development of effective ADCs requires the study of factors that can alter the stability of these therapeutics at the atomic level.

Computer Prediction of p Values in Small Molecules and Proteins.

Accurately determining the acid dissociation constants ( or their logarithmic form, p ) of small molecules and large biomolecules has proven to be pivotal for the study different biological processes and developing new drugs. This Viewpoint summarizes some of the most common methodologies and recent advances described for p prediction using computational techniques when experimental values are not easily accessible such as in proteins and/or for the screening of large libraries of new compounds.

Substrate Sequence Controls Regioselectivity of Lanthionine Formation by ProcM.

Lanthipeptides belong to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). The (methyl)lanthionine cross-links characteristic to lanthipeptides are essential for their stability and bioactivities. In most bacteria, lanthipeptides are maturated from single precursor peptides encoded in the corresponding biosynthetic gene clusters.

Nucleophilic catalysis of p-substituted aniline derivatives in acylhydrazone formation and exchange.

Hydrazone bond formation is a versatile reaction employed in several research fields. It is one of the most popular reversible reactions in dynamic combinatorial chemistry. Under physiological conditions, hydrazone exchange benefits from the addition of a nucleophilic catalyst.

Arylethynyltrifluoroborate Dienophiles for on Demand Activation of IEDDA Reactions.

Strained alkenes and alkynes are the predominant dienophiles used in inverse electron demand Diels-Alder (IEDDA) reactions. However, their instability, cross-reactivity, and accessibility are problematic. Unstrained dienophiles, although physiologically stable and synthetically accessible, react with tetrazines significantly slower relative to strained variants.