Periodic Reporting for period 1 - LABEL-DIOX (Late-stage catalytic carboxylation techniques with labelled carbon dioxide: new opportunities for radiolabelling)
Reporting period: 2017-12-01 to 2019-05-31
The evaluation of the metabolic profile of lead compounds through preclinical testing is of utmost importance in drug discovery. Although these studies require isotopically-labeled active pharmaceutical ingredients (APIs), their synthesis is oftentimes more problematic than that of the parent compound, reinforcing the need for strategies that rapidly and reliably incorporate isotopes into molecules. Among different scenarios, carbon labeling is often preferred due to its high sensitivity and lower risk of label metabolic cleavage, rendering the interpretation of preclinical data easy. While C-11 is utilized for positron emitting tomography (PET) imaging, its short half-life precludes long-term studies. However, C-13 and C-14 labeling are appropriate for evaluating drug profiles, including absorption, distribution, metabolism and excretion (ADME), and pharmacokinetic studies. Although radioactive C-14 has oftentimes displaced C-13 as metabolic tracers, recent advances in mass spectrometry and nuclear magnetic resonance has allowed the latter to be used for similar purposes, thus improving the practicality of these studies by employing stable C-13 probes.
Prompted by the prevalence of carboxylic acids in biologically active molecules, carboxylation reactions with isotopically-labeled carbon dioxide has attracted considerable attention. At present, high levels of C-13 and C–14 incorporation can be achieved with stoichiometric and polarized organometallics; however, their high reactivity and low chemoselectivity severely limits the synthetic application of these processes. Although decarboxylation allows carbon isotopes of carboxylic acids in drug molecules to be rapidly interchanged without modifying the established route to the drug molecule, such techniques require stoichiometric nickel species or harsh conditions. In addition, modest C-labeling exchange is observed due to competitive hydrolysis of the starting precursor or in situ carboxylation with initially extruded C-12 carbon dioxide. Taken together, these features contribute to the perception that designing a mild, robust and modular catalytic decarboxylation/carboxylation that enables the access to C–labeled aliphatic and aromatic carboxylic acids in high specific activities is deemed necessary. LABEL-DIOX provides a groundbreaking, unconventional and step-economical method for preparing carboxylic acids from labeled carbon dioxide from activated esters or halogenated species derived from carboxylic acids using earth-abundant metal catalysts (Ni) by merging decarboxylative events with carboxylation protocols with 13-C or 14-C labelled carbon dioxide. LABEL-DIOX is distinguished by their mild conditions, versatility, excellent chemoselectivity profile and high isotopic incorporations (up to >99% C-labeling), thus expediting the design of radiolabeling techniques – even in the context of late-stage functionalization – en route to labeled carboxylic acids while obviating the need for stoichiometric organometallic species. Given the prevalence of carboxylic acids in molecules that display important biological activities, LABEL-DIOX will change completely the way industrial chemists conduct radiolabelling of drugs containing carboxylic acids, a necessary step for ADME studies.
Prompted by the prevalence of carboxylic acids in biologically active molecules, carboxylation reactions with isotopically-labeled carbon dioxide has attracted considerable attention. At present, high levels of C-13 and C–14 incorporation can be achieved with stoichiometric and polarized organometallics; however, their high reactivity and low chemoselectivity severely limits the synthetic application of these processes. Although decarboxylation allows carbon isotopes of carboxylic acids in drug molecules to be rapidly interchanged without modifying the established route to the drug molecule, such techniques require stoichiometric nickel species or harsh conditions. In addition, modest C-labeling exchange is observed due to competitive hydrolysis of the starting precursor or in situ carboxylation with initially extruded C-12 carbon dioxide. Taken together, these features contribute to the perception that designing a mild, robust and modular catalytic decarboxylation/carboxylation that enables the access to C–labeled aliphatic and aromatic carboxylic acids in high specific activities is deemed necessary. LABEL-DIOX provides a groundbreaking, unconventional and step-economical method for preparing carboxylic acids from labeled carbon dioxide from activated esters or halogenated species derived from carboxylic acids using earth-abundant metal catalysts (Ni) by merging decarboxylative events with carboxylation protocols with 13-C or 14-C labelled carbon dioxide. LABEL-DIOX is distinguished by their mild conditions, versatility, excellent chemoselectivity profile and high isotopic incorporations (up to >99% C-labeling), thus expediting the design of radiolabeling techniques – even in the context of late-stage functionalization – en route to labeled carboxylic acids while obviating the need for stoichiometric organometallic species. Given the prevalence of carboxylic acids in molecules that display important biological activities, LABEL-DIOX will change completely the way industrial chemists conduct radiolabelling of drugs containing carboxylic acids, a necessary step for ADME studies.