Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.

Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy.

PURPOSE: Fibroblast activation protein (FAP) is a pan-cancer target and now the state-of-the-art to develop radiopharmaceuticals. FAP inhibitors have been of great success in developing imaging tracers. Yet, the overly rapid clearance cannot match with the long half-lives of regular therapeutic radionuclides. Though strategies that aim to elongate the circulation of FAPIs are being developed, here we describe an innovation that uses α-emitters of short half-lives (e.g., 213Bi) to pair the rapid pharmacokinetics of FAPIs. METHODS: An organotrifluoroborate linker is engineered to FAPIs to give two advantages: (1) selectively increases tumor uptake and retention; (2) facile 18F-radiolabeling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general. RESULTS: The organotrifluoroborate linker helps to improve the internalization in cancer cells, resulting in notably higher tumor uptake while the background is clean. In FAP-expressed tumor-bearing mice, this FAPI labeled with 213Bi, a short half-life α-emitter, exhibits almost complete suppression to tumor growth while the side effect is negligible. Additional data shows that this strategy is generally applicable to guide other α-emitters, such as 212Bi, 212Pb, and 149Tb. CONCLUSION: The organotrifluoroborate linker may be of importance to optimize FAP-targeted radiopharmaceuticals, and the short half-lived α-emitters may be of choice for the rapid-cleared small molecule-based radiopharmaceuticals.

Photocatalytic direct borylation of carboxylic acids.

The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO2 and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.

Metal-catalysed reactions enabled by guanidine-type ligands.

Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. As ligands, guanidines can have different coordination modes with the metal center. However, the exploitation of these guanidine complexes as catalysts has been much less successful. The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. The catalytic activities of metal-guanidinate complexes are of great interest to chemists. The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. This field is currently being pursued with great interest by synthetic organic chemists. In this review, the representative reactions enabled by guanidine and guanidinate metal complexes are highlighted.

Guanidine-Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates.

An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine-copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN 2' borylation process catalyzed by a monodentate guanidine-copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

(Guanidine)copper Complex-Catalyzed Enantioselective Dynamic Kinetic Allylic Alkynylation under Biphasic Condition.

Highly enantioselective allylic alkynylation of racemic bromides under biphasic condition is furnished in this report. This approach employs functionalized terminal alkynes as pro-nucleophiles and provides 6- and 7-membered cyclic 1,4-enynes with high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. Enantioretentive derivatizations highlight the synthetic utility of this transformation. Cold-spray ionization mass spectrometry (CSI-MS) and X-ray crystallography were used to identify some catalytic intermediates, which include guanidinium cuprate ion pairs and a copper-alkynide complex. A linear correlation between the enantiopurity of the catalyst and reaction product indicates the presence of a copper complex bearing a single guanidine ligand at the enantio-determining step. Further experimental and computational studies supported that the alkynylation of allylic bromide underwent an anti-SN2' pathway catalyzed by nucleophilic cuprate species. Moreover, metal-assisted racemization of allylic bromide allowed the reaction to proceed in a dynamic kinetic fashion to afford the major enantiomer in high yield.

Desiccation and cold storage of Galleria mellonella cadavers and effects on in vivo production of Steinernema carpocapsae.

BACKGROUND: Direct application of insect cadavers infected with entomopathogenic nematodes (EPN) can successfully control target pest insects. Little is known about the effects of environmental factors (desiccation and temperature) on the production process for infective juveniles (IJ) in insects. RESULTS: We examined the effects of desiccation time and cold storage (6.7 °C) on IJ production of the nematode Steinernema carpocapsae in Galleria mellonella cadavers at 30.8 and 57% humidity. Under desiccation, the IJ yield in cadavers increased gradually and reached a maximum on day 5. IJ yield gradually declined from day 6 onwards and was almost zero by day 15. In general, cold storage at 6.7 °C caused negative effects on IJ production in desiccated cadavers. Approximately 56 h post infection was the time at which nematodes were most sensitive to low temperatures during development in cadavers. Five-day desiccated cadavers generated higher mortality and more rapid death of Galleria mellonella larvae than using newly (day 0) desiccated cadavers. CONCLUSION: This study describe methods of optimizing rearing techniques such as desiccation and cold storage to promote the mass production and application of EPN- infected host cadavers for the field control of insect pests.