Late-Stage Fluorination: From Fundamentals to Application.
Ontology highlight
ABSTRACT: In this brief account, we review work from our lab with a focus on late-stage introduction of fluorine and fluorinated functional groups into small molecules. We attempt to highlight practical developments, which we believe may have potential for industrial applications, and critically reflect on developments that may not yet meet the bar for practical use.
Project description:A simple and easy-to-implement process based on a nucleophilic aromatic substitution reaction with a wide variety of nucleophiles on a fluorinated CinNapht is described. This process has the key advantage of introducing multiple functionalities at a very late stage, thus providing access to new applications including the synthesis of photostable and bioconjugatable large Stokes shift red emitting dyes and selective organelle imaging agents, as well as AIEE-based wash-free lipid droplet imaging in live cells with high signal-to-noise ratio. The synthesis of bench-stable CinNapht-F has been optimized and can be reproduced on a large scale, making it an easy-to-store starting material that can be used at will to prepare new molecular imaging tools.
Project description:Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.
Project description:Non-metallic catalysis has been known as a remarkable development strategy for hydrofunctionalization of unsaturated hydrocarbons. Herein, we report a unique chemically active method of BF3·OEt2 promoted multi-component, highly regioselective, and chemoselective hydrothio(seleo)phosphonylation of unsaturated hydrocarbons, which exhibits high yield and good substrate universality. The reaction mechanism was further elucidated to be Markovnikov addition by controlling experiments, 31P and 19F NMR spectra tracking experiments, X-ray diffraction analysis, and DFT calculations. Furthermore, the gram-scale attempt and the application of the reaction on the derivatization of natural products have been successfully conducted, leading to the discovery of 3as with potential anti-Parkinson's disease (PD) activities at 1 μM. This streamlined and efficient methodology has established a new platform for non-metallic Lewis acids-promoted hydrofunctionalization of unsaturated hydrocarbons and its application on new drug research.
Project description:Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
Project description:In order to identify genes with differential gene expression or alternative splicing between the groups Normal and late stage OSCC (Stage III and IV), we study 16 hybridizations (6 normal; 10 late stage OSCC) on the HumanGene10ST array using mixed model analysis of variance. 1323 genes with significant gene expression differences between the groups and 357 genes with significant exon-group interaction (a symptom of alternative splicing) were found, including 129 genes with both gene and possible splicing differences (p<0.01). Contingency table analysis of the set of studied genes and a dataset of known pathways and gene classifications revealed that the set of alternatively spliced and expressed genes were found to be significantly over-represented in groups of the GOMolFn, GOProcess, GOCellLoc, and Pathway classes (p<0.01). Algorithm ANOVA study of 16 HumanGene10ST files.
Project description:Common diseases with a genetic basis are likely to have a very complex etiology, in which the mapping between genotype and phenotype is far from straightforward. A new comprehensive statistical and computational strategy for identifying the missing link between genotype and phenotype has been proposed, which emphasizes the need to address heterogeneity in the first stage of any analysis and gene-gene interactions in the second stage. We applied this two-stage analysis strategy to late-onset Alzheimer disease (LOAD) data, which included functional and positional candidate genes and markers in a region of interest on chromosome 10. Bayesian classification found statistically significant clusterings for independent family-based and case-control datasets, which used the same five markers in leucine-rich repeat transmembrane neuronal 3 (LRRTM3) as the most influential in determining cluster assignment. In subsequent analyses to detect main effects and gene-gene interactions, markers in three genes--urokinase-type plasminogen activator (PLAU), angiotensin 1 converting enzyme (ACE) and cell division cycle 2 (CDC2)--were found to be associated with LOAD in particular subsets of the data based on their LRRTM3 multilocus genotype. All of these genes are viable candidates for LOAD based on their known biological function, even though PLAU, CDC2 and LRRTM3 were initially identified as positional candidates. Further studies are needed to replicate these statistical findings and to elucidate possible biological interaction mechanisms between LRRTM3 and these genes.
Project description:As an easily introduced noncoded amino acid with unique electrophilicity distinct from the 20 natural amino acids, dehydroalanine (Dha) is not only a precise protein post-translational modification (PTM) insertion tool, but also a promising multifunctional labelling site for peptides and proteins. However, achieving a balance between the reaction rate and mild reaction conditions has been a major challenge in developing novel Dha-modified strategies. Rapid, efficient, and mild Dha modification strategies are highly desired. Additionally, catalyst-free photocontrollable reactions for Dha-containing peptide and protein modification have yet to be developed. Here, we report a photoinitiated 1,3-dipolar cycloaddition reaction between Dha and 2,5-diaryl tetrazoles. Under low-power UV lamp irradiation, this reaction is completed within minutes without catalysis, resulting in a fluorescent pyrazoline-modified peptide or protein with excellent chemoselectivity for Dha residues. Notably, this reaction exhibits complete site-specificity in the modification of thiostrepton, a natural antimicrobial peptide containing multiple Dha residues (Dha3, Dha16, and Dha17), within 20 minutes in high yields. This is currently the fastest reaction for modifying the Dha residue in thiostrepton with clear site-specificity towards Dha16. This photoinitiated reaction also provides a chemoselective strategy for precise functionalization of proteins. Additionally, the rapidity and efficiency of the reaction minimize UV light damage to the biological reaction system. Combined with fluorogenic properties, this photo-controllable methodology can be applied to live cell imaging, further broadening the application scope of the Dha modification methodology.
Project description:The preparation of isotopically labeled compounds for drug discovery and development presents a unique challenge. Both stable and radioactive isotopes must be incorporated into complex bioactive molecules as efficiently as possible, using precious, and often expensive, isotopically enriched reagents. Due to the ubiquity and importance of methyl groups in drug molecules, there is a requirement for a general, late-stage methylation that allows for the incorporation of both carbon and hydrogen isotopes. Herein, we report a highly efficient, robust palladium-catalyzed approach, optimized via high-throughput experimentation, for the methylation of aryl chlorides using potassium methyltrifluoroborate. A practically straightforward route to isotopically labeled methylating agents has also been developed, and the methodology applied to isotopologue synthesis, including the installation of isotopic labels in a range of drug-like scaffolds.
Project description:To replace the conventional maximum tolerated dose (MTD) approach, a paradigm for dose optimization and dose selection that relies on model-informed drug development (MIDD) approaches has been proposed in oncology. Here, we report our application of an MIDD approach during phase I to inform dose selection for the late-stage development of datopotamab deruxtecan (Dato-DXd). Dato-DXd is a TROP2-directed antibody-drug conjugate being developed for advanced/metastatic non-small cell lung cancer (NSCLC) and other tumors. Data on pharmacokinetics (PKs), efficacy, and safety in NSCLC were collected in the TROPION-PanTumor01 phase I dose-expansion and -escalation study over a wide dose range of 0.27-10 mg/kg administered every 3 weeks. Population PK and exposure-response analyses were performed iteratively at three data cutoffs to inform dose selection. The 6 mg/kg dose was identified as the optimal dose by the second data cutoff analysis and confirmed by the subsequent third data cutoff analysis. The 6 mg/kg dose was more tolerable (i.e., lower rates of interstitial lung disease, stomatitis, and mucosal inflammation) than the MTD (8 mg/kg) and was more efficacious than 4 mg/kg (simulated mean objective response rate: 23.8% vs. 18.6%; mean hazard ratio of progression-free survival: 0.74) - a candidate dose studied just below 6 mg/kg. Therefore, the 6 mg/kg dose was judged to afford the optimal benefit-risk balance. This case study demonstrated the utility of an MIDD approach for dose optimization and dose selection.
Project description:Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here we present silver catalysis for carbon-fluorine bond formation. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date.