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Organic Letters Nov 2021Near-infrared (NIR) emitting fluorophores are powerful tools for optical imaging. However, there are only a handful of broadly employed NIR-emitting scaffolds, and the...
Near-infrared (NIR) emitting fluorophores are powerful tools for optical imaging. However, there are only a handful of broadly employed NIR-emitting scaffolds, and the synthetic methods to prepare these molecules are often problematic. Here, we describe a novel, three-step synthesis of chromene-containing hemicyanine probes exhibiting large Stokes shifts and NIR emissions. We develop a pH-activatable probe for visualizing lysosomal trafficking of mAb conjugates. These studies provide a concise approach to hemicyanines with promising properties.
Topics: Carbocyanines
PubMed: 34752112
DOI: 10.1021/acs.orglett.1c03367 -
Bioconjugate Chemistry Sep 2022The synthesis of radioimmunoconjugates via the stochastic attachment of bifunctional chelators to lysines can yield heterogeneous products with suboptimal and...
The synthesis of radioimmunoconjugates via the stochastic attachment of bifunctional chelators to lysines can yield heterogeneous products with suboptimal and behavior. In response to this, several site-selective approaches to bioconjugation have been developed, yet each has intrinsic drawbacks, such as the need for expensive reagents or the complexity of incorporating unnatural amino acids into IgGs. Herein, we describe the use of a simple and facile approach to lysine-directed site-selective bioconjugation for the generation of radioimmunoconjugates. This strategy relies upon on the selective modification of single lysine residues within each light chain of the monoclonal antibody (mAb) with a branched azide-bearing perfluorophenyl ester (PFP-bisN) followed by the ligation of dibenzocyclooctyne (DBCO)-bearing payloads to these bioorthogonal handles via the strain-promoted azide-alkyne cycloaddition. This methodology was used to create [Zr]Zr-DFO-pertuzumab, a radioimmunoconjugate of the HER2-targeting mAb pertuzumab labeled with desferrioxamine (DFO) and the positron-emitting radiometal zirconium-89 (Zr). [Zr]Zr-DFO-pertuzumab was compared to a pair of analogous probes: one synthesized via random lysine modification ([Zr]Zr-DFO-pertuzumab) and another via thiol-maleimide chemistry ([Zr]Zr-DFO-pertuzumab). The bioconjugation strategy was assessed using ESI mass spectrometry, SDS-PAGE, and autoradiography. All three immunoconjugates demonstrated comparable binding to HER2 via flow cytometry and surface plasmon resonance (SPR), and Zr-labeled variants of each were synthesized in >99% radiochemical yield and molar activities of up to ∼55.5 GBq/μmol (10 mCi/mg). Subsequently, the behavior of this trio of Zr-immunoPET probes was interrogated in athymic nude mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. [Zr]Zr-DFO-pertuzumab, [Zr]Zr-DFO-pertuzumab, and [Zr]Zr-DFO-pertuzumab produced positron emission tomography (PET) images with high tumoral uptake and high tumor-to-healthy organ activity concentration ratios. A terminal biodistribution study complemented the PET results, revealing tumoral activity concentrations of 126.9 ± 50.3%ID/g, 86.9 ± 53.2%ID/g, and 92.5 ± 27.2%ID/g at 144 h post-injection for [Zr]Zr-DFO-pertuzumab, [Zr]Zr-DFO-pertuzumab, and [Zr]Zr-DFO-pertuzumab, respectively. Taken together, the data clearly illustrate that this highly modular and facile approach to site-selective bioconjugation produces radioimmunoconjugates that are better-defined and more homogeneous than stochastically modified constructs and also exhibit excellent and performance. Furthermore, we contend that this lysine-directed strategy holds several key advantages over extant approaches to site-selective bioconjugation, especially in the context of production for the clinic.
Topics: Alkynes; Animals; Antibodies, Monoclonal; Azides; Breast Neoplasms; Cell Line, Tumor; Chelating Agents; Deferoxamine; Esters; Female; Humans; Immunoconjugates; Lysine; Maleimides; Mice; Mice, Nude; Positron-Emission Tomography; Sulfhydryl Compounds; Tissue Distribution; Zirconium
PubMed: 35946495
DOI: 10.1021/acs.bioconjchem.2c00354 -
The Journal of Organic Chemistry May 2022A series of [2]rotaxanes with various functional groups in the axle component was synthesized by the oxidative dimerization of alkynes, which is mediated by a...
A series of [2]rotaxanes with various functional groups in the axle component was synthesized by the oxidative dimerization of alkynes, which is mediated by a macrocyclic phenanthroline-Cu complex. The rotaxanes were fully characterized by spectroscopic methods, and the structure of a rotaxane was determined by X-ray crystallographic analysis. The interaction between the ring component and the axle component was studied in detail to understand the conformation of the rotaxanes. The presence of the hydrogen bond between the phenanthroline moiety in the macrocyclic component and the acidic proton in the axle component influenced the conformation of rotaxane.
Topics: Alkynes; Hydrogen Bonding; Molecular Conformation; Phenanthrolines; Rotaxanes
PubMed: 35389647
DOI: 10.1021/acs.joc.2c00086 -
International Journal of Molecular... May 2022Acetylenedicarboxylic acid dihydrate (ADAD) represents a complex with strong hydrogen bonding between the carboxylic OH and the water molecule. An X-ray re-examination...
Acetylenedicarboxylic acid dihydrate (ADAD) represents a complex with strong hydrogen bonding between the carboxylic OH and the water molecule. An X-ray re-examination of the ADAD crystal structure confirms the OO distance of the short hydrogen bonds, and clearly shows different bond lengths between the two oxygen atoms with respect to the carbon atom in the carboxyl group, indicating a neutral structure for the complex. The neutral structure was also confirmed by vibrational spectroscopy, as no proton transfer was observed. The diffraction studies also revealed two polymorph modifications: room temperature (α) and low temperature (β), with a phase transition at approximately 4.9 °C. The calculated vibrational spectra are in satisfactory agreement with the experimental spectra. A comparison of the structure and the vibrational spectra between the ADAD and the oxalic acid dihydrate reveals some interesting details. The crystal structures of both crystal hydrates are almost identical; only the OO distances of the strongest hydrogen bonds differ by 0.08 Å. Although it was expected that a larger OO spacing in the ADAD crystal may significantly change the infrared and Raman spectra, especially for the frequency and the shape of the acidic OH stretching vibration, both the shape and frequency are almost identical, with all subpeaks topped on the broad OH stretching vibration. The OO distance dependent are only in- and out-of-plane OH deformations modes. The presence of polarons due to the ionized defects was not observed in the vibrational spectra of ADAD. Therefore, the origin of the broad OH band shape was explained in a similar way to the acid dimers. The anharmonicity of a potential enhances the coupling of the OH stretching with the low-frequency hydrogen bond stretching, which, in addition to the Fermi resonance, structures the band shape of the OH stretching. The fine structure found as a superposition of a broad OH stretching is attributed to Davydov coupling.
Topics: Alkynes; Fatty Acids, Unsaturated; Hydrogen; Hydrogen Bonding; Vibration
PubMed: 35682843
DOI: 10.3390/ijms23116164 -
Molecules (Basel, Switzerland) May 2023Regio- and stereoselective switchable synthesis of ()- and ()--carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and...
Regio- and stereoselective switchable synthesis of ()- and ()--carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. AgCO plays a key role in the switchable synthesis of ()- and ()--carbonylvinylated pyrazoles. AgCO-free reactions lead to thermodynamically stable ()--carbonylvinylated pyrazoles in excellent yields whereas reactions with AgCO give ()--carbonylvinylated pyrazoles in good yields. It is noteworthy that ()- or ()--carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag acts as coordination guidance.
Topics: Pyrazoles; Stereoisomerism; Catalysis; Alkynes
PubMed: 37298822
DOI: 10.3390/molecules28114347 -
Angewandte Chemie (International Ed. in... Feb 2021By using Rh-H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters,...
By using Rh-H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters, with high enantio- and diastereocontrol. In this transformation, the alkyne undergoes isomerization to generate a Rh -π-allyl electrophile, which is trapped by an α-nitroester nucleophile. A subsequent reduction with In powder transforms the allylic α-nitroesters to the corresponding α,α-disubstituted α-amino esters.
Topics: Alkynes; Amino Acids; Catalysis; Coordination Complexes; Esters; Hydrogen; Rhodium; Stereoisomerism
PubMed: 33411337
DOI: 10.1002/anie.202014015 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2022The use of arylboron reagents in metal-catalyzed domino addition-cyclization reactions is a well-established strategy for the preparation of diverse, highly... (Review)
Review
The use of arylboron reagents in metal-catalyzed domino addition-cyclization reactions is a well-established strategy for the preparation of diverse, highly functionalized carbo- and heterocyclic products. Although rhodium- and palladium-based catalysts have been commonly used for these reactions, more recent work has demonstrated nickel catalysis is also highly effective, in many cases offering unique reactivity and access to products that might otherwise not be readily available. This review gives an overview of nickel-catalyzed arylative cyclizations of alkyne- and allene-tethered electrophiles using arylboron reagents. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described.
Topics: Alkadienes; Alkynes; Catalysis; Cyclization; Indicators and Reagents; Nickel; Rhodium
PubMed: 34986277
DOI: 10.1002/chem.202104230 -
Molecules (Basel, Switzerland) Jul 2021The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy... (Review)
Review
The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a -cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its -conformation via a radical catalyzed reaction. Unfortunately, the -conformer is significantly less reactive toward tetrazine than the -conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.
Topics: Alkynes; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Azides; Click Chemistry; Cycloaddition Reaction; Cyclooctanes; Electrons; Heterocyclic Compounds, 1-Ring; Humans; Hydrogen-Ion Concentration; Immunoconjugates; Molecular Targeted Therapy; Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents; Radioimmunotherapy
PubMed: 34361793
DOI: 10.3390/molecules26154640 -
Molecules (Basel, Switzerland) Apr 20203d transition metals-catalyzed C-H bond functionalizations represent nowadays an important tool in organic synthesis, appearing as the most promising alternative to... (Review)
Review
3d transition metals-catalyzed C-H bond functionalizations represent nowadays an important tool in organic synthesis, appearing as the most promising alternative to cross-coupling reactions. Among 3d transition metals, iron found widespread application due to its availability and benign nature, and it was established as an efficient catalyst in organic synthesis. In this context, the use of -orientating directing groups (DGs) turned out to be necessary for promoting selective iron-catalyzed C-H functionalization reactions. Very recently, triazoles DGs were demonstrated to be more than an excellent alternative to the commonly employed 8-aminoquinoline (AQ) DG, as a result of their modular synthesis as well as the mild reaction conditions applied for their removal. In addition, their tunable geometry and electronics allowed for new unprecedented reactivities in iron-catalyzed C-H activation methodologies that will be summarized within this review.
Topics: Alkadienes; Alkylation; Alkynes; Carbon; Catalysis; Hydrogen; Iron; Triazoles
PubMed: 32326406
DOI: 10.3390/molecules25081806 -
Journal of Medicinal Chemistry May 2023Combinatorial library screening increasingly explores chemical space beyond the Ro5 (bRo5), which is useful for investigating "undruggable" targets but suffers...
Combinatorial library screening increasingly explores chemical space beyond the Ro5 (bRo5), which is useful for investigating "undruggable" targets but suffers compromised cellular permeability and therefore bioavailability. Moreover, structure-permeation relationships for bRo5 molecules are unclear partially because high-throughput permeation measurement technology for encoded combinatorial libraries is still nascent. Here, we present a permeation assay that is scalable to combinatorial library screening. A liposomal fluorogenic azide probe transduces permeation of alkyne-labeled molecules into small unilamellar vesicles via copper-catalyzed azide-alkyne cycloaddition. Control alkynes (e.g., propargylamine, various alkyne-labeled PEGs) benchmarked the assay. Cell-permeable macrocyclic peptides, exemplary bRo5 molecules, were alkyne labeled and shown to retain permeability. The assay was miniaturized to microfluidic droplets with high assay quality (' ≥ 0.5), demonstrating excellent discrimination of photocleaved known membrane-permeable and -impermeable model library beads. Droplet-scale permeation screening will enable pharmacokinetic mapping of bRo5 libraries to build predictive models.
Topics: Alkynes; Azides; Catalysis; Copper; Gene Library; Liposomes; Peptides; Pharmacokinetics
PubMed: 37075027
DOI: 10.1021/acs.jmedchem.3c00138