The advent of bioorthogonal chemistry has revolutionized the common practices in protein bioconjugation and contributed to a large extent to the development of chemical biology, a discipline aimed at ...studying biological/biochemical processes/events in their natural setting (living cells, whole organisms) using dedicated chemical tools. This minireview intends to provide an up‐to‐date overview on the various bioorthogonal strategies implemented for the conjugation of transition organometallic entities to peptides, peptide nucleic acids and proteins with a focus on targeted applications, i.e. fluorescence‐ or radio‐labeling for imaging, controlled delivery of therapeutic agents and bioanalysis.
The recent developments in bioorthogonal ligations of transition organometallic complexes to peptides and proteins and their application in fluorescence or radioisotopic imaging and targeted delivery of pharmaceutical agents are reviewed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A general, sustainable dearomatization reaction for nitrogen‐containing heterocycles was developed. Under solvent free conditions and without catalyst, the biorenewable methyl coumalate (MC) reacted ...as an efficient C3 partner to convert nine types of basic aromatic rings into their pyrido1,2‐a fused derivatives in good to excellent yields. The fluorescence properties of some of the products were harnessed to conjugate fluorescent tags to bovine serum albumin (BSA) and immunoglobulin G.
No solvent, no catalyst: A single solvent‐free step starting from the biobased methyl coumalate enables the dearomatization of a broad range of heterocycles affording in high yields luminescent polycyclic compounds bearing a carboxylic acid function for later grafting onto biomolecules.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Owing to the intrinsic limitations of the conventional bioconjugation methods involving native nucleophilic functions of proteins, we sought to develop alternative approaches to introduce ...metallocarbonyl infrared labels onto proteins on the basis of the 3 + 2 dipolar azide‐alkyne cycloaddition (AAC). To this end, two cyclopentadienyl iron dicarbonyl (Fp) complexes carrying a terminal or a strained alkyne handle were synthesized. Their reactivity was examined towards a model protein and poly (amidoamine) (PAMAM) dendrimer, both carrying azido groups. While the copper (I)‐catalysed azide‐alkyne cycloaddition (CuAAC) proceeded smoothly with the terminal alkyne metallocarbonyl derivative, labelling by strain‐promoted azide‐alkyne cycloaddition (SPAAC) was less successful in terms of final coupling ratios. Infrared spectral characterization of the bioconjugates showed the presence of two bands in the 2000 cm−1 region, owing to the stretching vibration modes of the carbonyl ligands of the Fp entities.
Azide ‐ alkyne cycloadditions between BSA or PAMAM dendrimer carrying azide groups and cyclopentadienyl iron dicarbonyl (Fp) complexes carrying a terminal or a strained alkyne handle were examined. While the CuAAC proceeded smoothly, the SPAAC was less successful. Infrared spectra of the bioconjugates displayed two bands in the 2000 cm‐1 region, owing to the stretching vibration modes of the carbonyl ligands of the Fp entities.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Novel transition metallocarbonyl complexes carrying a norbornene or an oxanorbornene group were synthesized by 4 + 2 cycloaddition between the organometallic maleimide dienophiles and cyclopentadiene ...or furan, respectively. The oxanorbornene adduct was obtained as a mixture of endo and exo isomers as confirmed by X‐ray diffraction and NMR spectroscopy. The (oxa)norbornene groups further provided convenient chemical reporters to carry out inverse electron demand Diels‐Alder (iEDDA) reactions with tetrazine derivatives. Detailed kinetic studies with a model tetrazine revealed that faster rates of reaction were determined with both isomers of the oxanorbornene complex with respect to the norbornene complexes. Eventually, incorporation of metallocarbonyl entities into bovine serum albumin equipped with tetrazine handles was achieved as shown by IR spectroscopy of the protein conjugates.
A series of metallocarbonyl norbornenes was synthesized and their reactivity examined towards a model protein carrying the tetrazine entity. Infrared spectral characterization of the bioconjugates showed the presence of two characteristic bands in the 2000 cm−1 region confirming the successful labelling via iEDDA reaction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The first fluorescent ferrociphenol derivative (P797) has been synthesized via McMurry cross-coupling followed by copper-catalyzed 3 + 2 azide-alkyne cycloaddition of the fluorescent group coumarin. ...Cyclic voltammograms of P797 exhibit either a monoelectronic oxidation wave ascribed to the ferrocene Fe(II) → Fe(III) conversion or a three-electron oxidation process in the presence of a base, leading to a Fe(III) quinone methide adduct. This general sequence is consistent with those previously described for non-fluorescent ferrociphenols. Furthermore, the fluorescence properties of P797 and its oxidized intermediates appear to strongly depend on the redox state of the ferrocene group. Indeed, electrochemical generation of Fe(III) (ferrocenium) states markedly increases the fluorescence emission intensity. In contrast, the emission of the Fe(II) (ferrocene) states is partially quenched by photoinduced electron transfer (PET) from the Fe(II) donor to the coumarin acceptor and by concentration-dependent self-quenching. Owing to its switchable fluorescence properties, complex P797 could represent an innovative and useful tool to study the biodistribution and the redox state of ferrocifens in cancer cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We report a case of disseminated neuroblastoma (NB) causing epidural spinal cord compression in a 67-year-old woman. Because NB is primarily a tumor of infancy and childhood, less is known about its ...clinical course and optimal treatment in adults. This patient was treated with a thoracic laminectomy and tumor resection; polychemotherapy with one cycle of vindesine, cisplatin, and etoposide; one cycle of vincristine, dacarbazine, ifosfamide, and doxorubicin; and radiotherapy to the spine. She remained able to walk but died 8.5 months later of diffuse systemic tumor progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The Cover Feature shows how the Nature‐derived methylcoumalate reacts with N‐aromatics to provide fluorescent molecules helpful for bioimaging. More information can be found in the Communication by ...L. Chang et al.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We report the preparation of metal-carbonyl-dendrimer-antibody conjugates. These metal-carbonyl-multilabeled antibodies are designed to be used in a new solid-phase-format carbonyl metallo ...immunoassay (CMIA). A fourth-generation polyamidoamine dendrimer was labeled with 10-25 (η⁵-cyclopentadienyl)iron dicarbonyl (η¹-N-succinimidyl) entities. An antibody was chemically modified at its carbohydrate chains by a site-directed process used to preserve the antigen-antibody binding site. The antibody was then coupled with the dendrimer labeled with 10 metal carbonyl groups. An average of 1.4 labeled dendrimers were grafted per antibody molecule. These metal-carbonyl-dendrimer-antibody conjugates were used as new universal detection reagents that recognize their specific antigens. The antigens were spotted onto nitrocellulose membranes and detected by using the conjugates in combination with Fourier transform infrared spectroscopy. A detection level in the range 5-200 pmol per membrane was achieved. This approach opens the way to a new CMIA format.
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