Claudio Daniel Navo Nájera

Center for Cooperative Research in Biosciences | CIC bioGUNE · Chemistry

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 N-sulfonyl sulfamidates for the synthesis of cyclic lanthionine-containing peptides. The s...

Iridium‐catalyzed borylations of aromatic C–H bonds are highly attractive transformations owing to the diversification possibilities offered by the resulting boronates. These transformations are best carried out using bidentate bipyridine or phenanthroline ligands, and tend to be governed by steric factors, therefore resulting in the competitive fu...

Iridium‐catalyzed borylations of aromatic C–H bonds are highly attractive transformations owing to the diversification possibilities offered by the resulting boronates. These transformations are best carried out using bidentate bipyridine or phenanthroline ligands, and tend to be governed by steric factors, therefore resulting in the competitive fu...

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 (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we...

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...

Chemo- and diastereoselective 1,4-conjugate additions of anionic and radical C-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 tempera...

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...

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-benzylat...

Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-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 diastereo...

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....

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 stabi...

Accurately determining the acid dissociation constants (Ka or their logarithmic form, pKa) 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 pKa prediction using co...

In this article, the chemistry of 1,2,3-dithiazoles and 1,2,3-oxathiazoles is covered from 2009 to 2018 inclusive. The 1,2,3-dithiazoles studied are: 1,2,3-dithiazolium cations, 1,2,3-dithiazolyl radicals, 1,2,3-dithiazole-5-ones and related thiones, imines and ylidene compounds, their 5,5-disubstituted derivatives, and their 2-oxides. 1,2,3-Oxathi...

The first totally chemo- and diastereoselective 1,4-conjugate additions of Se-nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. The methodology is simple and does not require any catalyst, providing exceptional yields at room temperature, and involves the treatment of the corresponding diselenide compound with NaBH4 in the prese...

Adjuvants are key immunostimulatory components in vaccine formulations that improve the immune response to the co‐administered antigen. The saponin natural product QS‐21 is one of the most promising immunoadjuvants in the development of vaccines against cancer and infectious diseases but suffers from limitations that have hampered its widespread hu...

div> Protein conjugates are valuable tools to create therapeutics, such as antibody-drug conjugates, or to study biological processes. Despite a number of protein conjugation strategies having been developed over recent years, the ability to modify one specific amino acid on a protein in the presence of other side chains with similar reactivity re...

The chemistry of diazocompounds has generated a huge breadth of applications in the field of organic synthesis. Their versatility combined with their tuneable reactivity, stability and chemoselectivity makes diazo compounds desirable reagents for chemical biologists. Here, we describe a method for the precise installation of diazo-handles on protei...

The highly diastereoselective 1,4-conjugate additions of several nitrogen nucleophiles to chiral bicyclic dehydroalanines have been assessed effectively at room temperature in good to excellent yields without needing any catalyst or additional base. This methodology is general, simple, oxygen and moisture tolerant, high-yielding, totally chemo- and...

We have developed an azanorbornadiene bromovinyl sulfone reagent that allows cysteine‐selective bioconjugation. Subsequent reaction with dipyridyl tetrazine led to bond‐cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alde...

We have developed an azanorbornadiene bromovinyl sulfone reagent that allows cysteine‐selective bioconjugation. Subsequent reaction with dipyridyl tetrazine led to bond‐cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alde...

A hungry bear is trying to catch some slippery fish from a river; this resembles the feeling of bioorganic chemists attempting the synthesis of very reactive, elusive compounds such as the cyclic dehydroalanine derivatives (4‐methylenoxazol‐5(4H)‐ones). Non‐destructive detection techniques such as NMR spectroscopy (the fishing net) allowed us (the...

p>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 str...

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 and selective for cysteine relative to other amino acids that have nucleophilic side-chains, and the formed products are stable in human plasma...

Quaternised vinyl‐ and alkynyl‐pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine‐tagged proteins at near‐stoichiometric quantities. We have demonstrated that this method is able to create effectively a homogenous antibody‐drug conjugate that features a precise drug‐to‐antibody ratio of 2 that was stabl...

Quaternised vinyl‐ and alkynyl‐pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine‐tagged proteins at near‐stoichiometric quantities. We have demonstrated that this method is able to create effectively a homogenous antibody‐drug conjugate that features a precise drug‐to‐antibody ratio of 2 that was stabl...

In addition to its usage for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as a promising strategy to enable protein or drug activation in a spatially and temporally controlled manner. This study demonstrates the application of the bioorthogonal inverse electron‐demand Diels‐Alder (IEDDA) reaction to cleave trans‐...

For the first time, a simple methodology for the chemical synthesis and utilization of highly reactive 4‐methylen‐oxazol‐5(4H)‐ones from serine is presented. These dehydroalanine derivatives, which resemble the natural 4‐methylideneimidazole‐5‐one (MIO) cofactor present in lyases and aminomutases, undergo rapid reaction with carbon nucleophiles suc...

N-Acetylgalactosamine (GalNAc) α-O-linked to l-threonine (Thr) (Tn antigen) and several mimics of this Tn antigen have been synthesized to explore the impact of the underlying amino acid in the presentation mode of the carbohydrate moiety. The structural changes introduced in the Tn antigen mimics involve the replacement of the natural underlying T...

Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, an inhibitor of viral entry, a therapeutic for cystic fibrosis, and a tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalani...

Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal...

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 of aryl thiols to a chiral bicyclic dehydroalanine recently developed by our group. This reaction is fast at room temperature and proceeds with total chemo‐ and ster...

Glycocin F (GccF) is a unique diglycosylated bacteriocin peptide that possesses potent and reversible bacteriostatic activity against a range of Gram-positive bacteria. GccF is a rare example of a ‘glycoactive’ bacteriocin, with both the O-linked N-acetylglucosamine (GlcNAc) and the unusual S-linked GlcNAc moiety important for antibacterial activit...

The reactivity of cyclic tertiary sulfamidates derived from α-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring-opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both experimentally and computatio...

The chiral bicyclic dehydroalanine building block (I) is applied in stereoselective S-Michael reactions with a variety of thiols.

The first examples of amino acid (Ser/Thr)-sp²-iminosugar glycomimetic conjugates featuring an α-O-linked pseudoanomeric linkage are reported. The key synthetic step involves the completely diastereoselective α-glycosylation of Ser/Thr due to strong stereoelectronic and conformational bias imposed by the bicyclic sp²-iminosugar scaffold. Mucin-rela...

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 as GalNAc-α-SH) was used as a nucleophile. This addition proceeds with total chemo- and stereoselectivity, com...

A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-d-galactal, previously published by the authors. Stereoselective transformations of t...

A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold containing peptides is described. A peptide synthesis strategy allowing the rapid generation of mixed α/β-peptides incorporating a sulfamidate residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature of this scaffold...

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 to synthesize several pyrano[3,2-b]pyrrole structures. These scaffolds could be regarded as conformationally restricted Tn antigen mimics, as we have demonstrated by biological assays. The pyranose rings reta...