The combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor vascular disrupting agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to β-tubulin, believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.6b01128 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Photoclick and Release for Spatiotemporally Localized Theranostics of Single Cells via In Situ Generation of 1,3-Diaryl-1H-benzo[f]indazole-4,9-dione.
Angew Chem Int Ed Engl
November 2024
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, China.
Bioorthogonal click-release chemistry is a cutting-edge tool for exploring and manipulating biomolecule functions in native biological systems. However, it is challenging to achieve the precise regulation or therapy of individual cells via click-release strategies driven by proximity and thermodynamics. Herein, we propose a novel photoclick-release approach based on a photo-induced cycloaddition between 4,4'-bis(N-arylsydnone) or C-bithienyl-diarylsydnone and 2-arylamino-naphthoquinone via irradiation with 405 or 485 nm light.
View Article and Find Full Text PDFSydnone-based prosthetic groups for radioiodination.
Bioorg Med Chem
November 2024
Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA Nantes, France. Electronic address:
The potential of Strained-Promoted Sydnone-Alkyne Cycloaddition (SPSAC) for radioiodination was evaluated with model cyclooctyne-conjugated peptides. Starting with a series of sydnones with varying N and C substitution, a preliminary kinetic study with non-radioactive iodinated compounds highlighted the superiority of an arylsydnone substituted by a chlorine atom in C position. Interestingly, reaction rate up to 11 times higher than using an azide was achieved with the best system.
View Article and Find Full Text PDFIncorporation of Intracellular NanoSIMS Tracers to Oligonucleotide Conjugates via Strain Promoted Sydnone-Alkyne Cycloaddition.
Bioconjug Chem
July 2024
Medicinal Chemistry, Research and Development, Early Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, SE-431 83 Gothenburg, Sweden.
Extensive efforts have been dedicated to developing cell-specific targeting ligands that can be conjugated to therapeutic cargo, offering a promising yet still challenging strategy to deliver oligonucleotide therapeutics beyond the liver. Indeed, while the cargo and the ligand are crucial, the third component, the linker, is integral but is often overlooked. Here, we present strain-promoted sydnone-alkyne cycloaddition as a versatile linker chemistry for oligonucleotide synthesis, expanding the choices for bioconjugation of therapeutics while enabling subcellular detection of the linker and payload using nanoscale secondary ion mass spectrometry (NanoSIMS) imaging.
View Article and Find Full Text PDFExploration of the Copper-Catalyzed Sydnone and Sydnonimine-Alkyne Cycloaddition Reactions by High-Throughput Experimentation.
Chemistry
January 2024
CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SCBM, Université Paris Saclay, 91191, Gif-sur-Yvette, France.
The reactivity of sydnones and sydnonimines toward terminal alkynes under copper catalysis has been explored using High-Throughput-Experimentation. A large panel of ligands and reaction conditions have been tested to optimize the copper-catalyzed sydnone click reaction discovered by our group ten years ago. This screening approach led to the identification of new ligands, which boosted the catalytic properties of copper and allowed the discovery of a new copper-catalyzed click-and-release reaction involving sydnonimines.
View Article and Find Full Text PDF2'-Modified Thymidines with Bioorthogonal Cyclopropene or Sydnone as Building Blocks for Copper-Free Postsynthetic Functionalization of Chemically Synthesized Oligonucleotides.
Bioconjug Chem
September 2023
Université Paris-Saclay, CNRS, Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, 91405, Orsay, France.
The development of facile methods for conjugating relevant probes, ligands, or delivery agents onto oligonucleotides (ONs) is highly desirable both for fundamental studies in chemical biology and for improving the pharmacology of ONs in medicinal chemistry. Numerous efforts have been focused on the introduction of bioorthogonal groups onto phosphoramidite building blocks, allowing the controlled chemical synthesis of reactive ONs for postsynthetic modifications. Among these building blocks, alkyne, cyclooctynes, -cyclooctene, and norbornene have been proved to be compatible with automated solid-phase chemistry.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!