A5022377673- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Carbohydrate Chemistry and Synthesis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Synthesis and Catalytic Reactions
- Cyclopropane Reaction Mechanisms
- RNA and protein synthesis mechanisms
- Bioactive Compounds and Antitumor Agents
- Organic Chemistry Cycloaddition Reactions
- Asymmetric Synthesis and Catalysis
- Catalytic Cross-Coupling Reactions
- Oxidative Organic Chemistry Reactions
- Microbial Natural Products and Biosynthesis
- Synthesis and Biological Evaluation
- Computational Drug Discovery Methods
- Sulfur-Based Synthesis Techniques
- Chemical Synthesis and Reactions
- Catalytic C–H Functionalization Methods
- Synthesis and biological activity
- Ferrocene Chemistry and Applications
- Radical Photochemical Reactions
CIC bioGUNE
2019-2024
University of Auckland
2023
Ikerbasque
2021
Universidad de La Rioja
2013-2020
Boeing (Spain)
2020
Digital Research Alliance of Canada
2020
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, ability to modify one specific amino acid residue on a presence other reactive side chains remains challenge. We show that monosubstituted cyclopropenone (CPO) reagents react selectively with 1,2-aminothiol groups N-terminal cysteine residues give stable 1,4-thiazepan-5-one...
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 post-translationally modified peptide (RiPP), is produced by radical
Abstract Quaternized vinyl‐ and alkynyl‐pyridine reagents were shown to react in an ultrafast selective manner with several cysteine‐tagged proteins at near‐stoichiometric quantities. We have demonstrated that this method can effectively create a homogenous antibody–drug conjugate features precise drug‐to‐antibody ratio of 2, which was stable human plasma retained its specificity towards Her2+ cells. Finally, the developed warhead introduces +1 charge overall net protein, enabled us show...
Iridium-catalyzed borylations of aromatic C-H bonds are highly attractive transformations because the diversification possibilities offered by resulting boronates. These best carried out using bidentate bipyridine or phenanthroline ligands, and tend to be governed steric factors, therefore in competitive functionalization meta and/or para positions. We have now discovered that a subtle change ligand, namely, introduction CF3 substituent at position 5, enables complete regioselectivity...
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 to a carrier, which simultaneously masks underlying redox activity. C-benzylation at quinone carbonyl forms redox-inactive benzyl ketol. Upon specific enzymatic trigger, an acid-promoted, self-immolative C-C bond-cleaving 1,6-elimination...
The ability to control the activation of prodrugs by transition metals has been shown have great potential for controlled drug release in cancer cells. However, strategies developed so far promote cleavage C–O or C–N bonds, which limits scope drugs only those that present amino hydroxyl groups. Here, we report decaging an ortho-quinone prodrug, a propargylated β-lapachone derivative, through palladium-mediated C–C bond cleavage. reaction's kinetic and mechanistic behavior was studied under...
Replacing the <italic>O</italic>-linked saccharide in bacteriocin glycocin F with an <italic>S</italic>-linked version results a peptidomimetic that increases bacteriostatic effect.
The first examples of amino acid (Ser/Thr)–sp2-iminosugar glycomimetic conjugates featuring an α-O-linked pseudoanomeric linkage are reported. key synthetic step involves the completely diastereoselective α-glycosylation Ser/Thr due to strong stereoelectronic and conformational bias imposed by bicyclic sp2-iminosugar scaffold. Mucin-related glycopeptides incorporating these motifs were recognized monoclonal antibody (mAb) scFv-SM3, with activities depending on both hydroxylation pattern...
A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-d-galactopyranose (abbreviated GalNAc-α-SH) was used a nucleophile. This addition proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, at room temperature, making it true click reaction. The Michael adducts were transformed into...
An anti-cancer vaccine based on an unnatural antigen with sp<sup>2</sup>-iminosugar fragment.
Lanthipeptides belong to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). The (methyl)lanthionine cross-links characteristic lanthipeptides are essential for their stability bioactivities. In most bacteria, maturated from single precursor encoded in corresponding biosynthetic gene clusters. However, cyanobacteria engage combinatorial biosynthesis encode as many 80 substrate with highly diverse sequences that by a lanthionine synthetase into different...
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 target cell for maximum efficacy minimum toxicity. The development effective ADCs requires study factors can alter stability these at atomic level. Here, we present general strategy combines synthesis, bioconjugation, linker technology, site-directed mutagenesis, modeling investigate influence site...
We have developed [2.2.1]azabicyclic vinyl sulfone reagents that simultaneously enable cysteine-selective protein modification and introduce a handle for further bioorthogonal ligation. The reaction is fast selective cysteine relative to other amino acids nucleophilic side-chains, the formed products are stable in human plasma moderately resistant retro Diels-Alder degradation reactions. A model biotinylated reagent was shown efficiently label two cysteine-tagged proteins, ubiquitin C2Am,...
In addition to its use for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as a promising strategy enable protein or drug activation spatially and temporally controlled manner. This demonstrates application inverse electron-demand Diels-Alder (iEDDA) reaction cleave trans-cyclooctene (TCO) vinyl protecting groups from carboxylic acid-containing molecules. The tetrazine-mediated decaging proceeded under biocompatible conditions with fast kinetics (<2 min)....
Accurately determining the acid dissociation constants (Ka or their logarithmic form, pKa) of small molecules and large biomolecules has proven to be pivotal for study different biological processes developing new drugs. This Viewpoint summarizes some most common methodologies recent advances described pKa prediction using computational techniques when experimental values are not easily accessible such as in proteins and/or screening libraries compounds.
Abstract Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe novel multicomponent approach based on the combination isonitrile‐tetrazine (4+1) cycloaddition Ugi four‐component reaction to generate pyrazole amide derivatives. The scope as well mechanistic insights governing 4 H ‐pyrazol‐4‐imine tautomerization provided. This process provides access new space derivatives offers tool for peptide modification stapling.
Abstract An azanorbornadiene bromovinyl sulfone reagent for cysteine‐selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alder cycloaddition subsequent double retro‐Diels–Alder reactions form stable pyrrole linkage. sequence site‐selective followed by bioorthogonal was efficiently...
The synthesis of polysubstituted spirocyclopropyl oxindoles using a series rare-earth metal (REM) salts is reported. REMs, in particular Sc(OTf)3, allowed access to the target compounds by multicomponent reaction with high diastereoselectivity (≤94:6:0:0). Density functional theory calculations on model are consistent observed selectivity and revealed that special coordinating capabilities oxophilicity key factors inducing formation one main diastereoisomer.
A totally stereocontrolled C-Michael addition of serine-equivalent C-nucleophiles to tri-O-benzyl-2-nitro-d-galactal was used as the key step synthesize several pyrano[3,2-b]pyrrole structures. These scaffolds could be regarded conformationally restricted Tn antigen mimics, we have demonstrated by biological assays. The pyranose rings retain their (4)C1 chair conformation, shown molecular modeling and NMR spectroscopy. expected bioactivity established a competition-tailored enzyme-linked...
A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold containing peptides is described. synthesis strategy allowing the rapid generation of mixed α/β-peptides incorporating residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature this nucleophilic substitution at quaternary center with total inversion its configuration, which was demonstrated computationally, allows site-selective conjugation various...
A series of fluorescent d-cysteines (Cys) has been synthesized and their optical properties were studied. The key synthetic step is the highly diastereoselective 1,4-conjugate addition aryl thiols to a chiral bicyclic dehydroalanine recently developed by our group. This reaction fast at room temperature proceeds with total chemo- stereoselectivity. Michael adducts easily transformed into corresponding amino acids study and, in some selected cases, N-Fmoc-d-cysteine derivatives be used...
The first totally chemo- and diastereoselective 1,4-conjugate additions of Se-nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. methodology is simple does not require any catalyst, providing exceptional yields at room temperature, involves the treatment corresponding diselenide compound with NaBH4 in presence Dha. These Se-Michael provide an excellent channel for synthesis enantiomerically pure selenocysteine (Sec) derivatives, which pose high potential chemical biology...
The chemistry of diazo compounds has generated a huge breadth applications in the field organic synthesis. Their versatility combined with their tunable reactivity, stability, and chemoselectivity makes desirable reagents for chemical biologists. Here, we describe method precise installation handles on proteins antibodies mild specific approach. Subsequent 1,3-cycloaddition reactions strained alkynes enable both bioimaging through an in-cell "click" reaction probing cysteine proteome cell...
The highly diastereoselective 1,4-conjugate additions of several nitrogen nucleophiles to chiral bicyclic dehydroalanines have been assessed effectively at room temperature in good excellent yields without needing any catalyst or additional base. This methodology is general, simple, oxygen and moisture tolerant, high-yielding, totally chemo- stereoselective. procedure offers an efficient practical approach for the synthesis Nβ-substituted α,β-diamino acids, such as 1-isohistidine,...