Xinyne, a diaryl-N-methylamine analogue of isoCombretastatin A-4 was synthesized via a late-stage Cl-exchange using KCN. Xinyne exhibited potent antiproliferative activity at nanomolar concentrations against various human cancer cell lines, inhibited tubulin polymerization, induced apoptosis, and induced G2/M phase cell cycle arrest in 4T1 cells. To investigate its in vivo behavior, radiolabeled [14C]-Xinyne was prepared using [14C]-KCN. Pharmacokinetic analysis revealed significant sex-based differences: males showed faster absorption and more efficient elimination, whereas females exhibited broader tissue distribution and slower clearance. A biodistribution study demonstrated preferential accumulation of [14C]-Xinyne in the liver and the small intestine, with larger elimination through feces. Finally, the antitumor efficacy of Xinyne was confirmed in a murine breast cancer model.

In this work, we provide mild and direct access to carbon-labeled electrophilic cyanating agents suitable for both radioactive 14C and 11C. Carbon isotopes are at the foundation of applications in life science such as nuclear medicine and are essential for the determination of pharmacokinetic and dynamic profiles of new pharmaceuticals. While cyanations are key synthetic transformations in the arsenal of radiochemists, access to such precious building blocks still poses a severe challenge. Here, we report a two-step procedure that utilized [14C]CO2 and [11C]CO2 as primary isotope sources and takes place under exceptionally mild conditions compared to those of the state of the art. The utility of this procedure was demonstrated with the labeling of a panel of nitriles using traditional reactions as well as with unprecedented examples of carbon-isotope exchange.

The direct utilization of carbon dioxide as an ideal one-carbon source in value-added chemical synthesis has garnered significant attention from the standpoint of global sustainability. In this regard, the photo/electrochemical reduction of CO2 into useful fuels and chemical feedstocks could offer a great promise for the transition to a carbon-neutral economy. However, challenges in product selectivity continue to limit the practical application of these systems. A robust and general method for the conversion of CO2 to the polarity-reversed carbon dioxide radical anion, a C1 synthon, is critical for the successful valorization of CO2 to selective carboxylation reactions. We demonstrate herein a hydride and hydrogen atom transfer synergy driven general catalytic platform involving CO2 center dot- for highly selective anti-Markovnikov hydrocarboxylation of alkenes via triple photoredox, hydride, and hydrogen atom transfer catalysis. Mechanistic studies suggest that the synergistic operation of the triple catalytic cycle ensures a low-steady-state concentration of CO2 center dot- in the reaction medium. This method using a renewable light energy source is mild, robust, selective, and capable of accommodating a wide range of activated and unactivated alkenes. The highly selective nature of the transformation has been revealed through the synthesis of hydrocarboxylic acids from the substrates bearing a hydrogen atom available for intramolecular 1,n-HAT process as well as diastereoselective synthesis. This technology represents a general strategy for the merger of in situ formate generation with a synergistic photoredox and HAA catalytic cycle to provide CO2 center dot- for selective chemical transformations.

The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β-, t1/2 = 5730 years) as well as in positron emission tomography (PET) for in vivo molecular imaging applications (carbon-11, β+, t1/2 = 20.4 min). However, the structural diversity of radiotracers is still systematically driven by the narrow available labeled sources and methodologies. In this context, the emergence of carbon dioxide radical anion chemistry might set forth potential unexplored opportunities. Based on a dynamic isotopic equilibration between formate salts and [13C, 14C, 11C]CO2, C-labeled radical anion CO2•- could be accessed under extremely mild conditions within seconds. This methodology was successfully applied to hydrocarboxylation and dicarboxylation reactions in late-stage carbon isotope labeling of pharmaceutically relevant compounds. The relevance of the method in applied radiochemistry was showcased by the whole-body PET biodistribution profile of [11C]oxaprozin in mice.

Harvesting sunlight to drive carbon dioxide (CO 2 ) valorisation represents an ideal concept to support a sustainable and carbon-neutral economy. While the photochemical reduction of CO 2 to carbon monoxide (CO) has emerged as a hot research topic, the full CO 2 -to-CO conversion remains an often-overlooked criterion that prevents a productive and direct valorisation of CO into high-value-added chemicals. Herein, we report a photocatalytic process that unlocks full and fast CO 2 -to-CO conversion (<10 min) and its straightforward valorisation into human health related field of radiochemistry with carbon isotopes. Guided by reaction-model-based kinetic simulations to rationalize reaction optimisations, this manifold opens new opportunities for the direct access to 11 C- and 14 C-labeled pharmaceuticals from their primary isotopic sources [ 11 C]CO 2 and [ 14 C]CO 2 .

Carbon isotope labeling is a traceless technology, which allows tracking the fate of organic compounds either in the environment or in living organisms. Despite recent advances in the field, the development of robust and general technologies remains a significant task. This full article reports on a general approach to label urea derivatives with all carbon isotopes, including 14C and 11C. Based on a Staudinger aza-Wittig sequence, it provides access to all aliphatic/aromatic urea combinations as well as to semicarbazides, sulfonylureas, hydroxyl ureas, and simple terminal ureas. A de-risking approach was developed to evaluate the robustness of the reaction. This technology is based on [14C]CO2 screening that allowed to investigate the tolerance of the procedure with most representative heterocycles and functional groups found in FDA approved drugs.

A general procedure for the late-stage [11C], [13C] and [14C]carbon isotope labeling of cyclic carbamates is reported. This protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a direct, cost-effective and sustainable manner. A disconnection/reconnection strategy, involving ring opening/isotopic closure, was also implemented.

A transition-metal-free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2 , this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [14 C] and [13 C]. A proof of concept with [11 C] was also obtained with low molar activity valuable for distribution studies.

The understanding of the cellular uptake and the intracellular fate of nanoparticles and their subsequent influence on cell viability is challenging as far as micelles are concerned. Such systems are dynamic by nature, existing as unimers under their critical micelle concentration (CMC), and as micelles in equilibrium with unimers above the CMC, making canonical dose-response relationships difficult to establish. The purpose of this study was to investigate the in vitro cytotoxicity and uptake of two micellar sytems that are relevant for drug delivery. The two micelles incorporate a poly(ethylene glycol) coating and a pentacosadiynoic core which is either polymerized (pDA-PEG micelles) or non-polymerized (DA-PEG micelles), with the aim of evaluating the influence of the micelles status ("particle-like" or "dynamic", respectively) on their toxicological profile. Intracellular distribution and cytotoxicity of polymerized and non-polymerized micelles were investigated on RAW 264.7 macrophages in order to compare any different interactions with cells. Non-polymerized micelles showed significantly higher cytotoxicity than polymerized micelles, especially in terms of cell permeabilization, correlated to a higher accumulation in cell membranes. Other potential toxicity endpoints of polymerized micelles were then thoroughly studied in order to assess possible responses resulting from their endocytosis. No specific mechanisms of cytotoxicity were observed, neither in terms of apoptosis induction, cell membrane damage, release of inflammatory mediators nor genotoxicity. These data indicate that non-polymerized micelles accumulate in the cell membrane and induce cell membrane permeabilization, resulting in significant toxicity, whereas polymerized, stable micelles are internalized by cells but exert no or very low toxicity.

An integrated catalytic decarboxylation/carboxylation for accessing isotopically labeled carboxylic acids with (CO2)-C-13 or (CO2)-C-14 is described. The method shows a wide scope under mild conditions, even in the context of late-stage functionalization, and does not require stoichiometric organo-metallics, thus complementing existing carbon-labeling techniques en route to carboxylic acids.

A copper-catalyzed procedure enabling dynamic carbon isotope exchange is described. Utilizing the universal precursor [14C]CO2, this protocol allows to insert, in one single step, the desired carbon tag into carboxylic acids with no need of structural modifications. Reducing synthetic costs and limiting the generation of radioactive waste, this procedure will facilitate the access to carboxylic acids containing drugs and accelerate early 14C-based ADME studies supporting drug development.

AbstractA robust, click‐chemistry‐inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (11C, 13C, 14C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.

One-carbon metabolism is an ubiquitous metabolic pathway that encompasses the reactions transferring formyl-, hydroxymethyl- and methyl-groups bound to tetrahydrofolate for the synthesis of purine nucleotides, thymidylate, methionine and dehydropantoate, the precursor of coenzyme A. An alternative cyclic pathway was designed that substitutes 4-hydroxy-2-oxobutanoic acid (HOB), a compound absent from known metabolism, for the amino acids serine and glycine as one-carbon donors. It involves two novel reactions, the transamination of l-homoserine and the transfer of a one-carbon unit from HOB to tetrahydrofolate releasing pyruvate as coproduct. Since canonical reactions regenerate l-homoserine from pyruvate by carboxylation and subsequent reduction, every one-carbon moiety made available for anabolic reactions originates from CO2. The HOB-dependent pathway was established in an Escherichia coli auxotroph selected for prototrophy using long-term cultivation protocols. Genetic, metabolic and biochemical evidence support the emergence of a functional HOB-dependent one-carbon pathway achieved with the recruitment of the two enzymes l-homoserine transaminase and HOB-hydroxymethyltransferase and of HOB as an essential metabolic intermediate. Escherichia coli biochemical reprogramming was achieved by minimally altering canonical metabolism and leveraging on natural selection mechanisms, thereby launching the resulting strain on an evolutionary trajectory diverging from all known extant species.

A convenient one-pot synthetic access to 2-aminobenzoxazoles and 2-aminobenzothiazoles has been developed. The protocol uses KCN as starting material and proceeds through an in situ polarity inversion step. This approach provides a new valuable and straightforward entry to carbon-14-radiolabeled pharmaceutically relevant heterocycles and substantially reduces as well the amount of radioactive wastes generated.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 58, Issue 4 p. 147-155 Abstracts Abstracts of the 23rd International Isotope Society (UK group) Symposium: synthesis and applications of labelled compounds 2014 A. Anwar, A. AnwarSearch for more papers by this authorS. Archibald, S. ArchibaldSearch for more papers by this authorD. Audisio, D. AudisioSearch for more papers by this authorG. Badman, G. BadmanSearch for more papers by this authorJ. Bergin, J. BerginSearch for more papers by this authorS. P. Bew, S. P. BewSearch for more papers by this authorJ. Bloom, J. BloomSearch for more papers by this authorN. Bushby, N. BushbySearch for more papers by this authorA. Busigin, A. BusiginSearch for more papers by this authorM. Y. T. Chan, M. Y. T. ChanSearch for more papers by this authorJ. Davies, J. DaviesSearch for more papers by this authorJ. Dilworth, J. DilworthSearch for more papers by this authorM. Dunscombe, M. DunscombeSearch for more papers by this authorC. S. Elmore, C. S. ElmoreSearch for more papers by this authorP. Engstrom, P. EngstromSearch for more papers by this authorM. J. Fuchter, M. J. FuchterSearch for more papers by this authorN. J. Geach, N. J. GeachSearch for more papers by this authorD. Georgin, D. GeorginSearch for more papers by this authorA. Griffiths, A. GriffithsSearch for more papers by this authorP. Hansen, P. HansenSearch for more papers by this authorG. Hardcastle, G. HardcastleSearch for more papers by this authorG. D. Hiatt-Gipson, G. D. Hiatt-GipsonSearch for more papers by this authorM. J. Hickey, M. J. HickeySearch for more papers by this authorS. L. Kitson, S. L. KitsonSearch for more papers by this authorA. Lashford, A. LashfordSearch for more papers by this authorE. Lenz, E. LenzSearch for more papers by this authorS. Lewinton, S. LewintonSearch for more papers by this authorW. J. S. Lockley, Corresponding Author W. J. S. Lockley Correspondence to: W. J. S. Lockley, Division of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. E-mail: w.lockley@surrey.ac.ukSearch for more papers by this authorO. Loreau, O. LoreauSearch for more papers by this authorS. Maddocks, S. MaddocksSearch for more papers by this authorP. Marlière, P. MarlièreSearch for more papers by this authorA. McEwen, A. McEwenSearch for more papers by this authorT. S. Moody, T. S. MoodySearch for more papers by this authorP. Morgan, P. MorganSearch for more papers by this authorS. J. Roe, S. J. RoeSearch for more papers by this authorD. J. Schenk, D. J. SchenkSearch for more papers by this authorD. J. Speed, D. J. SpeedSearch for more papers by this authorR. A. Stockman, R. A. StockmanSearch for more papers by this authorK. Sumal, K. SumalSearch for more papers by this authorF. Taran, F. TaranSearch for more papers by this authorS. Thurston, S. ThurstonSearch for more papers by this authorM. Waring, M. WaringSearch for more papers by this authorW. H. Watters, W. H. WattersSearch for more papers by this author A. Anwar, A. AnwarSearch for more papers by this authorS. Archibald, S. ArchibaldSearch for more papers by this authorD. Audisio, D. AudisioSearch for more papers by this authorG. Badman, G. BadmanSearch for more papers by this authorJ. Bergin, J. BerginSearch for more papers by this authorS. P. Bew, S. P. BewSearch for more papers by this authorJ. Bloom, J. BloomSearch for more papers by this authorN. Bushby, N. BushbySearch for more papers by this authorA. Busigin, A. BusiginSearch for more papers by this authorM. Y. T. Chan, M. Y. T. ChanSearch for more papers by this authorJ. Davies, J. DaviesSearch for more papers by this authorJ. Dilworth, J. DilworthSearch for more papers by this authorM. Dunscombe, M. DunscombeSearch for more papers by this authorC. S. Elmore, C. S. ElmoreSearch for more papers by this authorP. Engstrom, P. EngstromSearch for more papers by this authorM. J. Fuchter, M. J. FuchterSearch for more papers by this authorN. J. Geach, N. J. GeachSearch for more papers by this authorD. Georgin, D. GeorginSearch for more papers by this authorA. Griffiths, A. GriffithsSearch for more papers by this authorP. Hansen, P. HansenSearch for more papers by this authorG. Hardcastle, G. HardcastleSearch for more papers by this authorG. D. Hiatt-Gipson, G. D. Hiatt-GipsonSearch for more papers by this authorM. J. Hickey, M. J. HickeySearch for more papers by this authorS. L. Kitson, S. L. KitsonSearch for more papers by this authorA. Lashford, A. LashfordSearch for more papers by this authorE. Lenz, E. LenzSearch for more papers by this authorS. Lewinton, S. LewintonSearch for more papers by this authorW. J. S. Lockley, Corresponding Author W. J. S. Lockley Correspondence to: W. J. S. Lockley, Division of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. E-mail: w.lockley@surrey.ac.ukSearch for more papers by this authorO. Loreau, O. LoreauSearch for more papers by this authorS. Maddocks, S. MaddocksSearch for more papers by this authorP. Marlière, P. MarlièreSearch for more papers by this authorA. McEwen, A. McEwenSearch for more papers by this authorT. S. Moody, T. S. MoodySearch for more papers by this authorP. Morgan, P. MorganSearch for more papers by this authorS. J. Roe, S. J. RoeSearch for more papers by this authorD. J. Schenk, D. J. SchenkSearch for more papers by this authorD. J. Speed, D. J. SpeedSearch for more papers by this authorR. A. Stockman, R. A. StockmanSearch for more papers by this authorK. Sumal, K. SumalSearch for more papers by this authorF. Taran, F. TaranSearch for more papers by this authorS. Thurston, S. ThurstonSearch for more papers by this authorM. Waring, M. WaringSearch for more papers by this authorW. H. Watters, W. H. WattersSearch for more papers by this author First published: 12 March 2015 https://doi.org/10.1002/jlcr.3276Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume58, Issue4April 2015Pages 147-155 RelatedInformation

The development of robust and straightforward methods to efficiently label aromatic moieties starting from simple and convenient radio-synthetic sources still represents a considerable challenge. In this report, a new palladium-catalyzed decarboxylative cyanation protocol has been described. This procedure utilizes [(14)C]-labeled potassium cyanide, one of the simplest and commercially available sources of carbon-14. Under the optimized reaction conditions, a series of [(13)C] and [(14)C]-aromatic nitriles were easily prepared (12-74% yield starting from potassium cyanide). The usefulness of this methodology is highlighted by a rare example of a formal two-step [(12)C]-[(14)C] carbon isotope exchange. The current synthetic approach may represent a promising alternative to traditional preparations of relevant building blocks such as labeled aromatic nitriles.

Adenosine is a pleiotropic endogenous nucleoside with potential neuroprotective pharmacological activity. However, clinical use of adenosine is hampered by its extremely fast metabolization. To overcome this limitation, we recently developed a new squalenoyl nanomedicine of adenosine [Squalenoyl-Adenosine (SQAd)] by covalent linkage of this nucleoside to the squalene, a natural lipid. The resulting nanoassemblies (NAs) displayed a dramatic pharmacological activity both in cerebral ischemia and spinal cord injury pre-clinical models. The aim of the present study was to investigate the plasma profile and tissue distribution of SQAd NAs using both Squalenoyl-[3H]-Adenosine NAs and [14C]-Squalenoyl-Adenosine NAs as respective tracers of adenosine and squalene moieties of the SQAd bioconjugate. This study was completed by radio-HPLC analysis allowing to determine the metabolization profile of SQAd. We report here that SQAd NAs allowed a sustained circulation of adenosine under its prodrug form (SQAd) for at least 1h after intravenous administration, when free adenosine was metabolized within seconds after injection. Moreover, the squalenoylation of adenosine and its formulation as NAs also significantly modified biodistribution, as SQAd NAs were mainly captured by the liver and spleen, allowing a significant release of adenosine in the liver parenchyma. Altogether, these results suggest that SQAd NAs provided a reservoir of adenosine into the bloodstream which may explain the previously observed neuroprotective efficacy of SQAd NAs against cerebral ischemia and spinal cord injury.