Diastereoselective Access to Ester-Substituted cis-Phenanthridinones via Hydrogen Atom Transfer-Involved 1,7-Enyne Bicyclization.

An organophotoredox-catalyzed 1,7-enyne bicyclization for the cis-diastereoselective synthesis of ester-substituted phenanthridinones has been achieved through radical cascade cyclization involving 1,6-hydrogen atom transfer. This transition-metal- and oxidant-free one-pot protocol generates three distinct C-C bonds and two quaternary carbon centers.

Visible light-enabled synthesis of phosphorylated indolizine and pyridoindole derivatives via HAT-mediated radical cascade cyclization.

A visible light-enabled cascade cyclization strategy is disclosed with concomitant phosphorylation and heterocycle construction. It provides a novel and environmentally benign approach for accessing tetrahydroindolizine-containing phosphonates under metal-free conditions. Mechanistic studies revealed that phosphinoyl radicals were generated from H-phosphonates via a HAT process.

Photoredox-Catalyzed Three-Component 1,2-Cyanoalkylpyridylation of Styrenes with Nonredox-Active Cyclic Oximes.

Three-component alkene 1,2-difunctionalizations have emerged as a powerful strategy for rapid buildup of diverse and complex alkylpyridines, but the distal functionalized alkyl radicals for the alkene 1,2-alkylpyridylations were still rare. Herein, we report an example of regioselective three-component 1,2-cyanoalkylpyridylation of feedstock styrenes with accessible nonredox-active cyclic oximes through visible-light photoredox catalysis, providing a series of structurally diverse ß-cyanoalkylated alkylpyridines. This protocol proceeds through a radical relay pathway including the generation of iminyl radicals enabled by phosphoranyl radical-mediated ß-scission, radical transposition through C-C bond cleavage, highly selective radical addition, and precise radical-radical cross-coupling sequence, thus facilitating the regioselective formation of two distinct C-C single bonds in a single-pot operation. This synthetic strategy features mild conditions, broad compatibility of functional groups and substrate scope, diverse product derivatization, and late-stage modification.

Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO3 Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity.

Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO3-PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.

Randomized, double-blinded, placebo-controlled phase I study of the pharmacokinetics, pharmacodynamics, and safety of KL130008, a novel oral JAK inhibitor, in healthy subjects.

BACKGROUND AND OBJECTIVES: KL130008 is a novel selective inhibitor of Janus kinase (JAK) 1/2 that may have therapeutic benefit against rheumatoid arthritis (RA) and other autoimmune diseases. Here, we developed a first-in-human trial of KL130008 to evaluate its pharmacokinetics (PK), pharmacodynamics (PD), and safety in healthy subjects. METHODS: Randomized, double-blinded, placebo-controlled phase I study was designed. Healthy Chinese subjects received KL130008 in single-ascending doses (1-20 mg) or multiple-ascending doses (2-6 mg) once daily for seven days, and data on PK, PD, and safety data including QT interval were evaluated. RESULTS: A total of 79 subjects were enrolled, of whom 77 completed the study. After oral administration following at least a 10-h fast, KL130008 was rapidly absorbed and reached a maximum concentration (Cmax) in 0.6-1.5 h. KL130008 exposure was approximately linear and dose-proportional. The drug showed exponential elimination with t1/2 = 14-18 h, and 8-20% of KL130008 was excreted in the urine. Dose-dependent inhibition of the phosphorylated signal transduction and transcriptional activator 3 (p-STAT3) was observed in subjects who received single KL130008 doses of 4-20 mg, while multiple dosing of KL130008 at 2, 4, or 6 mg once daily for seven consecutive days sustainably inhibited p-STAT3. The rates of treatment-emergent adverse events were 88.7% with KL130008 and 81.3% with placebo. All such events were grade 1 or 2 and disappeared or resolved by the end of the study. The most frequent such events were a decrease in neutrophil percentage, which occurred in 30.6% of subjects on KL130008; a decrease in neutrophil count, which occurred in 29.0% of subjects on KL130008; and an increase in lymphocyte percentage, which occurred in 25.8% of subjects on KL130008. None of these three events occurred while subjects were on placebo. CONCLUSION: Our results support that KL130008 is a safe and well-tolerated oral JAK1/2 inhibitor. The present study may help optimize the KL130008 dosing regimen for a phase II study. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1800018743 (chictr.org); registered on October 7, 2018.

Vitamin C supramolecular hydrogel for enhanced cancer immunotherapy.

Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors.

Epigenetic Platinum Complexes Breaking the "Eat Me/Don't Eat Me" Balance for Enhanced Cancer Chemoimmunotherapy.

Platinum complexes, despite being the most successful organometallic anticancer chemotherapy drugs, still suffer from serious side effects and therapy resistance. Inspired by the immunomodulation effect of platinum drugs, an epigenetic platinum(IV) complex was synthesized for enhanced cancer chemoimmunotherapy by conjugating oxidized oxaliplatin (OXA) with 2-bromo-1-(3,3-dinitro-1-azetidinyl)ethenone (RRx-001), the latter of which as a nitric oxide (NO) donor is also an epigenetic agent. The obtained complex (named OXA-NO) could significantly increase the level of "eat me" signal CRT expression and decrease the level of "don't eat me" signal CD47 expression on cancer cell membranes to promote their phagocytosis by macrophages. In addition, OXA-NO could release nitric oxide to trigger the transformation of pro-tumorigenic M2-type macrophages into antitumor M1-type macrophages within the tumor to reverse the immunosuppressive tumor microenvironment. Compared to commercial OXA, OXA-NO exhibited much stronger tumor growth inhibition ability and was much better tolerated, with obviously weakened side effects observed in spleen, lung, and kidneys. Therefore, this epigenetic platinum(IV) complex that exhibits excellent therapeutic efficacy and safety has great potential in the clinic.

Injectable Reactive Oxygen Species-Responsive SN38 Prodrug Scaffold with Checkpoint Inhibitors for Combined Chemoimmunotherapy.

Chemotherapeutic agents have been widely used for cancer treatment in clinics. Aside from their direct cytotoxicity to cancer cells, some of them could activate the immune system of the host, contributing to the enhanced antitumor activity. Here, the reactive oxygen species (ROS)-responsive hydrogel, covalently cross-linked by phenylboronic acid-modified 7-ethyl-10-hydroxycamptothecin (SN38-SA-BA) with poly(vinyl alcohol) (PVA), is fabricated for topical delivery of anti-programmed cell death protein ligand 1 antibodies (aPDL1). In the presence of endogenous ROS, SN38-SA-BA will be oxidized and hydrolyzed, leading to the degradation of hydrogel and the release of initial free SN38 and encapsulated aPDL1. It is demonstrated that SN38 could elicit specific immune responses by triggering immunogenic cell death (ICD) of cancer cells, a distinct cell death pathway featured with the release of immunostimulatory damage-associated molecular patterns (DAMPs). Meanwhile, the released aPDL1 could bind to programmed cell death protein ligand 1 (PDL1) expressed on cancer cells to augment antitumor T cell responses. Thus, the ROS-responsive prodrug hydrogel loaded with aPDL1 could induce effective innate and adaptive antitumor immune responses after local injection, significantly inhibiting or even eliminating those tumors.

CaCO3-Assisted Preparation of pH-Responsive Immune-Modulating Nanoparticles for Augmented Chemo-Immunotherapy.

Due to the negative roles of tumor microenvironment (TME) in compromising therapeutic responses of various cancer therapies, it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment. Herein, we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method, thereby enabling effective co-encapsulation of both doxorubicin (DOX), an immunogenic cell death (ICD) inducer, and alkylated NLG919 (aNLG919), an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). The obtained DOX/aNLG919-loaded CaCO3 nanoparticles (DNCaNPs) are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1. Upon intravenous injection, such DNCaNPs show efficient tumor accumulation, improved tumor penetration of therapeutics and neutralization of acidic TME. As a result, those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+ cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy & immunotherapy. This study presents a compendious strategy for construction of pH-responsive nanoparticles, endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.