Hydrogen Isotope Labeling of Pharmaceuticals Via Dual Hydrogen Isotope Exchange Pathways Using CdS Quantum Dot Photocatalyst.

Isotopic labeling is a powerful technique extensively used in the pharmaceutical industry. By tracking isotope-labeled molecules, researchers gain unique and invaluable insights into the pharmacokinetics and pharmacodynamics of new drug candidates. Hydrogen isotope labeling is particularly important as hydrogen is ubiquitous in organic molecules in biological systems, and it can be introduced effectively through late-stage hydrogen isotope exchange (HIE).

Homogenous Palladium-Catalyzed Dehalogenative Deuteration and Tritiation of Aryl Halides with D/T Gas.

Hydrogen isotopically labeled compounds have extensive utility across diverse domains, especially in drug discovery and development. However, synthesis of the labeled compounds with exclusive site selectivity and/or high isotope incorporation is challenging. One widely employed method is heterogeneous palladium(0)-catalyzed (such as Pd/C) dehalogenative deuteration and tritiation with D/T gas.

Chemoenzymatic synthesis and immunological evaluation of sialyl-Thomsen-Friedenreich (sTF) antigen conjugate to CRM197.

sTF (sialyl-Thomsen-Friedenreich) is a type of tumor-associated carbohydrate antigens (TACAs) and is highly expressed in various human malignancies. To validate if sTF could be a valuable molecular target for future cancer vaccine development, in this work the sTF antigen was prepared by adopting a strategy combining chemical and enzymatic methods, and then was covalently conjugated to a carrier protein, CRM197. The preliminary immunological evaluation, performed on BALB/c mice, revealed that the sTF-CRM197 conjugate elicited high titers of specific IgG antibodies.

The novel selective TLR7 agonist GY101 suppresses colon cancer growth by stimulating immune cells.

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells.

An Investigation of Instability in Dried Blood Spot Samples for Pharmacokinetic Sampling in Phase 3 Trials of Verubecestat.

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability.

Efficient Aliphatic Hydrogen-Isotope Exchange with Tritium Gas through the Merger of Photoredox and Hydrogenation Catalysts.

Employment of a combination of an organophotoredox catalyst with Wilkinson's catalyst (Rh(PPh)Cl) has given rise to an unprecedented method for hydrogen-isotope exchange (HIE) of aliphatic C(sp)-H bonds of complex pharmaceuticals using T gas directly. Wilkinson's catalyst, commonly used for catalytic hydrogenations, was exploited as a precatalyst for activation of D or T and hydrogen atom transfer. In this combined methodology and mechanistic study, we demonstrate that by coupling photocatalysis with Rh catalysis, carbon-centered radicals generated via photoredox catalysis can be intercepted by Rh-hydride intermediates to deliver an effective hydrogen atom donor for hydrogen-isotope labeling of complex molecules in one step.

Direct β-Mannosylation of Primary Alcohol Acceptors: Trisaccharide Iteration Assembly of β-1,6-Oligomannosides Corresponding to Kakelokelose.

Gold(I)-catalyzed stereoselective β-glycosylation of primary alcohols is achieved using the orthogonally protected mannosyl α--hexynylbenzoate (OABz) donors devoid of 4,6--tethering groups used in conventionally constructing β-mannosidic bonds. The potential of this methodology is showcased by the first assembly of β-1,6-tri/hexa-/nonamannosides and related sulfated congeners through a convergent strategy. The synthesis features the stereocontrolled β-glycosylation of α-trimannosyl OABz donors and the late-stage sulfonation.

The PET tracer [C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [C]MK-6884 from rhesus monkeys to patients with Alzheimer’s disease (AD). [H]MK-6884/[C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo.

Conjugate of ibrutinib with a TLR7 agonist suppresses melanoma progression and enhances antitumor immunity.

The use of large molecules for immunotherapy has led to exciting developments in cancer treatment, such as the development of PD-1/PD-L1 antibodies. However, small molecule targeted therapies still lack effective immune-functional classes. Ideal anticancer drugs should simultaneously generate immune memory when killing cancer cells to prevent tumor relapse and metastasis.

Discovery of novel ibrutinib analogues to treat malignant melanoma.

A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC value in B16 cells was almost 9-fold better than that of ibrutinib. Mechanism of action studies showed that YL7 inhibited proliferation and migration and induced G1 cell cycle arrest, apoptosis and autophagy in B16 cells.

Synthesis and biological evaluation of novel cabazitaxel analogues.

Cabazitaxel is one of the most recently FDA-approved taxane anticancer agent. In view of the advantages in preclinical and clinical data of cabazitaxel over former toxoids, the synthesis and biological evaluation of novel cabazitaxel analogues were conducted. First, a novel semi-synthesis of cabazitaxel was described.

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C-CN Bond Activation.

A facile one-pot strategy for CN and CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN) to facilitate enrichment using the nonlabeled parent compound as the starting material, eliminating synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach.

Late-Stage O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway.

A late-stage O labeling approach of sulfonamides that employs the corresponding unlabeled molecule as the starting material was developed. Upon deamination of the sulfonamide, a sulfinate intermediate was isotopically enriched using eco-friendly reagents H O and NH (aq) to afford a M+5 isotopologue of the parent compound. This degradation-reconstruction approach afforded isolated yields of up to 96 % for the stable isotope labeled (SIL) sulfonamides, and was compatible with multiple marketed therapeutics, including celecoxib, on a gram scale.

Synthesis and biological evaluation of Ginsenoside Compound K analogues as a novel class of anti-asthmatic agents.

Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities.

Glycosylation of a Ketone with an O-Glycosyl Trichloroacetimidate Provides an Enol Glycoside.

An enol-type glycosylation reaction has been investigated. Enol glycosides can be obtained from the reaction between O-glycosyl trichloroacetimidates and the corresponding ketones promoted by an acid. The enol glycosides derived from cyclic ketones can be afforded efficiently and isolated in good yield, while those from acyclic ketones are prepared in low conversion or are too labile for isolation.

Synthesis and biological evaluation of novel larotaxel analogues.

Taxoids are a class of successful drugs and have been successfully used in chemotherapy for a variety of cancer types. However, despite the hope and promises that these taxoids have engendered, their utility is hampered by some clinic limitations. Extensive structure-activity relationship (SAR) studies of toxoids have been performed in many different laboratories.

Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner.

Background/aims: Genistein is a natural isoflavone enriched in soybeans. It has beneficial effects for patients with mucopolysaccharidose type III through inhibiting glycosaminoglycan biosynthesis. However, other studies indicate that genistein does not always inhibit glycosaminoglycan biosynthesis.

S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds.

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H, C, and N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of S.

Concise total synthesis of acylated phenolic glycosides vitexnegheteroin A and ovatoside D.

Starting from readily available vanillin and α-D-acetobromo glucose, two natural acylated phenolic glycosides vitexnegheteroin A and ovatoside D were synthesized for the first time in 4 steps with overall yields of 54% and 65%, respectively. The key steps involve the directly regioselective O-6 acylation of vanillin β-D-glucopyranoside with acyl chlorides, and simultaneous removal of the allyl protecting groups on the phenolic acid moiety and reduction of the aldehyde in the aglycon moiety by using Pd(PPh)-NaBH system in one pot.

Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via KSO-Mediated Oxidative Radical Decarboxylation of Uronic Acids.

We have developed an efficient protocol for the synthesis of C-glycosylated phenanthridines. Tetrafuranos-4-yl and pentapyranos-5-yl radicals, generated from KSO-mediated oxidative decarboxylation of furan- and pyranuronic acids, undergo attack to 2-isocyanodiphenyls and ensuing homolytic aromatic substitution to provide diverse C-glycosylated phenanthridines in satisfactory yields without resort to transition metals. This reaction tolerates various functional groups, and enables ready synthesis of complex oligosaccharide-based phenanthridines.

Heparan Sulfate and Chondroitin Sulfate Glycosaminoglycans Are Targeted by Bleomycin in Cancer Cells.

Background/aims: Bleomycin is a clinically used anti-cancer drug that produces DNA breaks once inside of cells. However, bleomycin is a positively charged molecule and cannot get inside of cells by free diffusion. We previously reported that the cell surface negatively charged glycosaminoglycans (GAGs) may be involved in the cellular uptake of bleomycin.

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions.

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)/(,)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (,)-QuinoxP*·PdBr complex.

Synthesis of [(14) C]omarigliptin.

An efficient synthesis for [(14) C]Omarigliptin (MK-3102) is described. The initial synthesis of a key (14) C-pyrazole moiety did not work due to the lack of stability of (14) C-DMF-DMA reagent. Thus, a new radiolabeled synthon, (14) C-biphenylmethylformate, was synthesized from (14) C-sodium formate in one step in 92% yield and successfully used in construction of the key (14) C-pyrazole moiety.

Synthesis and DNA-binding properties of novel DNA cyclo-intercalators containing purine-glucuronic acid hybrids.

Novel DNA cyclo-intercalators, which incorporated two intercalator subunits linked by two bridges, were synthesized. Binding of the compounds to calf-thymus DNA was studied by fluorescence spectroscopy, and docking simulations were used to predict the binding modes of these cyclic compounds. The spectral data demonstrated that all of these compounds can interact with CT-DNA.