Annealing 1,2,4-triazine to iridium(III) complexes induces luminogenic behaviour in bioorthogonal reactions with strained alkynes.

A phenanthroline-type ligand containing an annealed 1,2,4-triazine ring was used to prepare novel Ir(III) complexes 3 and 4. The complexes are non-luminescent but show luminogenic behaviour following the inverse electron demand Diels-Alder (IEDDA) reaction with bicyclononyne (BCN) derivatives. It was observed that the complexes react with BCN-C10 faster than the corresponding free ligands.

Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies.

The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps.

Optical modulation of cell nucleus penetration and singlet oxygen release of a switchable platinum complex.

The activation of anticancer molecules with visible light constitutes an elegant strategy to target tumors and to improve the selectivity of treatments. In this context, we report here a visible-light activatable bis-platinum complex () incorporating an organic photo-switchable ligand based on the dimethyldihydropyrene moiety. Illumination of this metal complex with red light (660 nm) under air readily produces the corresponding endoperoxide form ().

Metabolic labelling of cancer cells with glycodendrimers stimulate immune-mediated cytotoxicity.

The recruitment of antibody naturally present in human blood stream at the surface of cancer cells have been proved a promising immunotherapeutic strategy to fight cancer. Antibody recruiting molecules (ARMs) combining tumor and antibody binding modules have been developed for this purpose, however the formation of the interacting complex with both antibody and cell is difficult to optimize to stimulate immune-mediated cytotoxicity. To circumvent this limitation, we report herein a more direct approach combining cell metabolism of azido-sugar and bio-orthogonal click chemistry to conjugate at the cell glycocalyx structurally well-defined glycodendrimers as antibody binding module (ABM).

Correction: Antibody recruiting molecules (ARMs): synthetic immunotherapeutics to fight cancer.

[This corrects the article DOI: 10.1039/D1CB00007A.].

Antibody recruiting molecules (ARMs): synthetic immunotherapeutics to fight cancer.

Antibody-recruiting molecules (ARMs) are one of the most promising tools to redirect the immune response towards cancer cells. In this review, we aim to highlight the recent advances in the field. We will illustrate the advantages of different ARM approaches and emphasize the importance of a multivalent presentation of the binding units.

Structural influence of antibody recruiting glycodendrimers (ARGs) on antitumoral cytotoxicity.

The recruitment of endogenous antibodies against cancer cells has become a reliable antitumoral immunotherapeutic alternative over the last decade. The covalent attachment of antibody and tumor binding modules (ABM and TBM) within a single, well-defined synthetic molecule was indeed demonstrated to promote the formation of an interacting ternary complex between both the antibodies and the targeted cell, which usually results in the simultaneous immune-mediated cellular destruction. In a preliminary study, we have described the first Antibody Recruiting Glycodendrimers (ARGs), combining cRGD as ligands for the αVβ3-expressing melanoma cell line M21 and Rha as ligand for natural IgM, and demonstrated that multivalency is an essential requirement to form this complex.

Chemical synthesis and immunological evaluation of new generation multivalent anticancer vaccines based on a Tn antigen analogue.

Tumor associated carbohydrate antigens (TACAs), such as the Tn antigen, have emerged as key targets for the development of synthetic anticancer vaccines. However, the induction of potent and functional immune responses has been challenging and, in most cases, unsuccessful. Herein, we report the design, synthesis and immunological evaluation in mice of Tn-based vaccine candidates with multivalent presentation of the Tn antigen (up to 16 copies), both in its native serine-linked display (Tn-Ser) and as an oxime-linked Tn analogue (Tn-oxime).

Redox-Active Bis-Cyclometalated Iridium(III) Complex as a DNA Photo-Cleaving Agent.

The development of new photoactive metal complexes that can trigger oxidative damages to the genetic material is of great interest. In the present paper, we describe the detailed study of a highly photo-oxidant iridium(III) complex that triggers photoinduced electron transfer (PET) with purine DNA bases. The PET has been studied by luminescence and laser flash photolysis experiments.

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells.

Invited for the cover of this issue is Olivier Renaudet and co-workers at the Université Grenoble Alpes and funded by the European Research Council (CoG "LEGO'" no. 647938). The image illustrates a synthetic chemist playing with supramolecular structures to kill cancer cells by using natural antibodies present in the blood stream.

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells.

We have developed a fully synthetic and multifunctional antibody-recruiting molecule (ARM) to guide natural antibodies already present in the blood stream against cancer cells without pre-immunization. Our ARM is composed of antibody and tumor binding modules (i.e.

Towards the preparation of synthetic outer membrane vesicle models with micromolar affinity to wheat germ agglutinin using a dialkyl thioglycoside.

A series of alkyl thioglycosides and alkyl thiodiglycosides bearing glucose and -acetylglucosamine residues were prepared by thiol-ene coupling in moderate to good yields (40-85%). Their binding ability towards wheat germ agglutinin was measured by competitive enzyme-linked lectin assays. One of the synthetic compounds presenting two GlcNAc units showed the highest inhibitory effect of this study with an IC of 11 µM corresponding to a 3182-fold improvement compared to GlcNAc.

Copper(II) complexes of NO tripodal ligands appended with pyrene and polyamine groups: Anti-proliferative and nuclease activities.

A series of tripodal ligands based on the 2-tert-butyl-4-R-6-phenol was synthesized, where R=aldehyde (HL), R=putrescine-pyrene (HL) and R=putrescine (HL). A dinucleating ligand wherein a putrescine group connects two tripodal moieties was also prepared (HL). The corresponding copper complexes (1, 2, 3, and 4, respectively) were prepared and characterized.

Heterovalent Glycodendrimers as Epitope Carriers for Antitumor Synthetic Vaccines.

The large majority of TACA-based (TACA=Tumor-Associated Carbohydrate Antigens) antitumor vaccines target only one carbohydrate antigen, thereby often resulting in the incomplete destruction of cancer cells. However, the morphological heterogeneity of the tumor glycocalix, which is in constant evolution during malignant transformation, is a crucial point to consider in the design of vaccine candidates. In this paper, an efficient synthetic strategy based on orthogonal chemoselective ligations to prepare fully synthetic glycosylated cyclopeptide scaffolds grafted with both Tn and TF antigen analogues is reported.

Cyclopeptide scaffolds in carbohydrate-based synthetic vaccines.

Cyclopeptides have been recently used successfully as carriers for the multivalent presentation of carbohydrate and peptide antigens in immunotherapy. Beside their synthetic versatility, these scaffolds are indeed interesting due to their stability against enzyme degradation and low immunogenicity. This mini-review highlights the recent advances in the utilization of cyclopeptides to prepare fully synthetic vaccines prototypes against cancers and pathogens.

A high-throughput screen for detection of compound-dependent phosphodiester bond cleavage at abasic sites.

We have employed a DNA molecular beacon with a real abasic site, namely a 2-deoxyribose, in a fluorescent high-throughput assay to identify artificial nucleases that cleave at abasic sites. We screened a 1280 compound chemical library and identified a compound that functions as an artificial nuclease. We validated a key structure-activity relationship necessary for abasic site cleavage using available analogs of the identified artificial nuclease.

Divergent and convergent synthesis of GalNAc-conjugated dendrimers using dual orthogonal ligations.

The synthesis of glycodendrimers remains a challenging task. In this paper we propose a protocol based on both oxime ligation (OL) to combine cyclopeptide repeating units as the dendritic core and the copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) to conjugate peripheral α and β propargylated GalNAc. By contrast with the oxime-based iterative protocol reported in our group, our current strategy can be used in both divergent and convergent routes with similar efficiency and the resulting hexadecavalent glycodendrimers can be easily characterized compared to oxime-linked analogues.

Multivalent glycocyclopeptides: toward nano-sized glycostructures.

Cyclopeptides have recently emerged as attractive molecular scaffolds for the multivalent presentation of carbohydrates in a well-defined constrained spatial orientation. This mini-review describes the last advances on the synthesis and the biological applications of these particular structures, going from low molecular weight glycoclusters to fully synthetic nano-sized glycodendrimers.

Expanding the scope of oxime ligation: facile synthesis of large cyclopeptide-based glycodendrimers.

A new series of 64-valent glycodendrimers was prepared in excellent yield and purity using a divergent and iterative strategy based on oxime ligation. Enzyme-linked lectin assays revealed the first nanomolar inhibitor for the fucose-specific lectin isolated from Ulex europaeus.

Tetravalent glycocyclopeptide with nanomolar affinity to wheat germ agglutinin.

A series of tetravalent glycocyclopeptides functionalized with GlcNAc was synthesized using copper(i)-catalysed alkyne-azide cycloaddition, oxime ligation and thiol-ene coupling. The binding ability of these compounds towards wheat germ agglutinin was studied by a competitive ELLA test and ITC experiments. While all compounds were able to inhibit WGA binding to GlcNAc-polymer coated surfaces at low concentrations, derivative 17 having an aliphatic spacer and thioether linkage was 4.

High affinity glycodendrimers for the lectin LecB from Pseudomonas aeruginosa.

Following an iterative oxime ligation procedure, cyclopeptide (R) and lysine-based dendron (D) were combined in all possible arrangements and successively functionalized with α-fucose and β-fucose to provide a new series of hexadecavalent glycosylated scaffolds (i.e., scaffolds RD16, RR16, DR16, and DD16).

Nuclease and anti-proliferative activities of copper(II) complexes of N3O tripodal ligands involving a sterically hindered phenolate.

Copper(II) complexes 1(2+)-6 of a series of tripodal ligands involving a N3O donor set, namely 2-[(bis-pyridin-2-ylmethyl-amino)-methyl]-4-methoxy-phenol (1L), 2-tert-butyl-4-methoxy-6-[bis-pyridin-2-ylmethyl-amino)-methyl]-phenol (2L), 2-tert-butyl-4-methoxy-6-{[(2-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (3L), 2-tert-butyl-4-methoxy-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (4L), 2-tert-butyl-4-fluoro-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (5L) and 2-tert-butyl-4-methoxy-6-{bis[(6-methyl-pyridin-2-ylmethyl)-amino]-methyl}-phenol (6L), respectively, were synthesized. Complexes 1(2+), 3(+) and 4(+) were structurally characterized by X-ray diffraction. The structure of 1(2+) is dimeric, with an essentially trigonal bipyramidal geometry around the copper(II) ions and two bridging deprotonated phenolate moieties.

Glycoside and peptide clustering around the octasilsesquioxane scaffold via photoinduced free-radical thiol-ene coupling. The observation of a striking glycoside cluster effect.

Two series of multivalent octasilsesquioxane glyco- and peptido-conjugates were synthesized using the photoinduced free-radical thiol-ene coupling (TEC). The first series was obtained by coupling C-glycosylpropyl thiols and cysteine containing peptides with the known octavinyl octasilsesquioxane while the second series was obtained by reacting glycosyl thiols with a new octasilsesquioxane derivative displaying eight PEGylated chains functionalized with terminal allyl groups. The evaluation of the binding properties of mannoside and glucoside clusters toward Concanavalin A by Enzyme-Linked Lectin Assay (ELLA) revealed a modest glycoside cluster effect.

Dendri-RAFTs: a second generation of cyclopeptide-based glycoclusters.

Synthetic glycoclusters and their related biological applications have stimulated increasing interest over the last decade. As a prerequisite to discovering active and selective therapeuticals, the development of multivalent glycoconjugates with diverse topologies is faced with inherent synthetic and structural characterisation difficulties. Here we describe a new series of molecularly-defined glycoclusters that were synthesized in a controlled manner using a robust and versatile divergent protocol.

Chemical synthesis, DNA incorporation and biological study of a new photocleavable 2'-deoxyadenosine mimic.

The phototriggered cleavage of chemical bonds has found numerous applications in biology, particularly in the field of gene sequencing through photoinduced DNA strand scission. However, only a small number of modified nucleosides that are able to cleave DNA at selected positions have been reported in the literature. Herein, we show that a new photoactivable deoxyadenosine analogue, 3-nitro-3-deaza-2'-deoxyadenosine (d(3-NiA)), was able to induce DNA backbone breakage upon irradiation (lambda > 320 nm).