In vivo three-dimensional brain imaging with chemiluminescence probes in Alzheimer's disease models.

Optical three-dimensional (3D) molecular imaging is highly desirable for providing precise distribution of the target-of-interest in disease models. However, such 3D imaging is still far from wide applications in biomedical research; 3D brain optical molecular imaging, in particular, has rarely been reported. In this report, we designed chemiluminescence probes with high quantum yields, relatively long emission wavelengths, and high signal-to-noise ratios to fulfill the requirements for 3D brain imaging in vivo. With assistance from density-function theory (DFT) computation, we designed ADLumin-Xs by locking up the rotation of the double bond via fusing the furan ring to the phenyl ring. Our results showed that ADLumin-5 had a high quantum yield of chemiluminescence and could bind to amyloid beta (Aß). Remarkably, ADLumin-5's radiance intensity in brain areas could reach 4 × 107 photon/s/cm2/sr, which is probably 100-fold higher than most chemiluminescence probes for in vivo imaging. Because of its strong emission, we demonstrated that ADLumin-5 could be used for in vivo 3D brain imaging in transgenic mouse models of Alzheimer's disease.

HN-PPISP: a hybrid network based on MLP-Mixer for protein-protein interaction site prediction.

MOTIVATION: Biological experimental approaches to protein-protein interaction (PPI) site prediction are critical for understanding the mechanisms of biochemical processes but are time-consuming and laborious. With the development of Deep Learning (DL) techniques, the most popular Convolutional Neural Networks (CNN)-based methods have been proposed to address these problems. Although significant progress has been made, these methods still have limitations in encoding the characteristics of each amino acid in protein sequences. Current methods cannot efficiently explore the nature of Position Specific Scoring Matrix (PSSM), secondary structure and raw protein sequences by processing them all together. For PPI site prediction, how to effectively model the PPI context with attention to prediction remains an open problem. In addition, the long-distance dependencies of PPI features are important, which is very challenging for many CNN-based methods because the innate ability of CNN is difficult to outperform auto-regressive models like Transformers. RESULTS: To effectively mine the properties of PPI features, a novel hybrid neural network named HN-PPISP is proposed, which integrates a Multi-layer Perceptron Mixer (MLP-Mixer) module for local feature extraction and a two-stage multi-branch module for global feature capture. The model merits Transformer, TextCNN and Bi-LSTM as a powerful alternative for PPI site prediction. On the one hand, this is the first application of an advanced Transformer (i.e. MLP-Mixer) with a hybrid network for sequence-based PPI prediction. On the other hand, unlike existing methods that treat global features altogether, the proposed two-stage multi-branch hybrid module firstly assigns different attention scores to the input features and then encodes the feature through different branch modules. In the first stage, different improved attention modules are hybridized to extract features from the raw protein sequences, secondary structure and PSSM, respectively. In the second stage, a multi-branch network is designed to aggregate information from both branches in parallel. The two branches encode the features and extract dependencies through several operations such as TextCNN, Bi-LSTM and different activation functions. Experimental results on real-world public datasets show that our model consistently achieves state-of-the-art performance over seven remarkable baselines. AVAILABILITY: The source code of HN-PPISP model is available at https://github.com/ylxu05/HN-PPISP.

Ligand-Oxidation-Based Anodic Synthesis of Oriented Films of Conductive M-Catecholate Metal-Organic Frameworks with Controllable Thickness.

Effective control over the crystallization of metal-organic framework (MOF) films is of great importance not only for the performance study and optimization in related applications but also for the fundamental understanding of the involved reticular chemistry. Featuring many technological advantages, electrochemical synthesis has been extensively reported for many MOF materials but is still challenged by the production of dense oriented films with a large-range tuning of thickness. Here, we report a ligand-oxidation-based anodic strategy capable of synthesizing oriented films of two-dimensional (2D) and three-dimensional (3D) conductive M-catecholate MOFs (2D Cu3(HHTP)2, 2D Zn3(HHTP)2, 2D Co3(HHTP)2, 3D YbHHTP, and 2D Cu2TBA) with tunable thicknesses up to tens of micrometers on commonly used electrodes. This anodic strategy relies on the oxidation of redox-active catechol ligands and follows a stepwise electrochemical-chemical reaction mechanism to achieve effective control over crystallizing M-catecholate MOFs into films oriented in the [001] direction. Benefiting from the electrically conductive nature, Cu3(HHTP)2 films could be thickened at a steady rate (17.4 nm·min-1) from ∼90 nm to 10.7 µm via a growth mechanism differing from those adopted in previous electrochemical synthesis of dense MOF films with limited thickness due to the self-inhibition effect. This anodic synthesis could be further combined with a templating strategy to fabricate not only films with well-defined 2D features in sizes from micrometers to millimeters but also high aspect ratio mesostructures, such as nanorods, of Cu3(HHTP)2.

A new histone deacetylase inhibitor remodels the tumor microenvironment by deletion of polymorphonuclear myeloid-derived suppressor cells and sensitizes prostate cancer to immunotherapy.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. METHODS: We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. RESULTS: We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. CONCLUSIONS: Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.

Noninvasive Positron Emission Tomography Imaging of SIRT1 in a Model of Early-Stage Alcoholic Liver Disease.

Accrued evidence has indicated that epigenetic mechanisms altered by alcohol have been implicated in the progression and development of alcoholic liver disease (ALD). SIRT1 plays an important role in ALD progression and has emerged as a promising therapeutic target for treating ALD. The purpose of this study is to investigate the efficacy of [11C]WL-1 for quantitative imaging of SIRT1 in mouse models of early-stage ALD. Positron emission tomography/computerized tomography (PET/CT) imaging was carried out 60 min following the injection of [11C]WL-1 in mouse models of early-stage ALD and normal control mice. The time-activity curves for ALD mouse livers showed remarkably decreased total uptake of [11C]WL-1 relative to that for control mouse livers. Moreover, compared with the normal control mice, decreased uptake in the cortex, hippocampus, and cerebellum was also observed in early-stage ALD mice, while the uptake of [11C]WL-1 in amygdala showed no significant changes. Western blot analysis confirmed that the protein levels of SIRT1 in the brains of early-stage ALD mice were decreased significantly when compared to the normal control mouse brains. Collectively, PET imaging with [11C]WL-1 would facilitate future clinical studies, aiming to demonstrate the roles of SIRT1 in ALD.

Design of Smartphone-Assisted Point-of-Care Platform for Colorimetric Sensing of Uric Acid via Visible Light-Induced Oxidase-Like Activity of Covalent Organic Framework.

Monitoring of uric acid (UA) levels in biological samples is of great significance for human health, while the development of a simple and effective method for the precise determination of UA content is still challenging. In the present study, a two-dimensional (2D) imine-linked crystalline pyridine-based covalent organic framework (TpBpy COF) was synthesized using 2,4,6-triformylphloroglucinol (Tp) and [2,2'-bipyridine]-5,5'-diamine (Bpy) as precursors via Schiff-base condensation reactions and was characterized with scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDS), Powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, and Brunauer-Emmett-Teller (BET) assays. The as-synthesized TpBpy COF exhibited excellent visible light-induced oxidase-like activity, ascribed to the generation of superoxide radicals (O2•-) by photo-generated electron transfer. TpBpy COF could efficiently oxidase the colorless substrate 3,3',5,5'-tetramethylbenzydine (TMB) into blue oxidized TMB (oxTMB) under visible light irradiation. Based on the color fade of the TpBpy COF + TMB system by UA, a colorimetric procedure was developed for UA determination with a detection limit of 1.7 µmol L-1. Moreover, a smartphone-based sensing platform was also constructed for instrument-free and on-site detection of UA with a sensitive detection limit of 3.1 µmol L-1. The developed sensing system was adopted for UA determination in human urine and serum samples with satisfactory recoveries (96.6-107.8%), suggesting the potential practical application of the TpBpy COF-based sensor for UA detection in biological samples.

PET Imaging of Bromodomain and Extra-Terminal Domain Inhibitors for the Noninvasive Assessment of Metabolic Changes in the Liver and Brain of Early-Stage Alcoholic Liver Disease.

Alcoholic liver disease (ALD) has a significant impact on human health and is one of the leading causes of liver disease mortality. The early and exact diagnosis of ALD is very important since the early stage of disease progression can be reversible. Although ALD can be evaluated by ultrasound, CT, or MRI, there is still no imaging technique sufficient in the diagnosis of early-stage ALD. Of the current studies, epigenetic modulation plays a significant role in the development and progression of ALD. In this work, we evaluate whether BRDs play a vital role in the early-stage ALD using our new PET imaging probe of BET proteins, [11C]CW22. PET/CT imaging of [11C]CW22 and [18F]FDG was used to identify early-stage lesions of livers and brains in the mice model. We found that the average uptake values of livers and brains in early-stage ALD were significantly increased for [11C]CW22 PET/CT imaging but only slightly changed in [18F]FDG PET/CT imaging. Consistently, we also found that BRD 3, 4 protein expression levels were significantly higher in the liver and brain tissues of early-stage ALD. Furthermore, through Pmod software, we found that [11C]CW22 PET/CT uptakes in the brain stem, cerebellum, and midbrain were significantly up-regulated in the early-stage ALD. In conclusion, BRDs were important mediators of damage in early-stage ALD. [11C]CW22 PET/CT imaging can detect the early-phase alcohol-induced damage of livers and brains, which will likely lead to human trials in the future.

Preliminary studies of an imidazole-based alcohol derivative for imaging of Heme oxygenase 1.

Heme oxygenase-1 (HO-1) has been involved in the pathogenesis of Alzheimer's disease (AD), thus constituting a promising target for AD drug development. Positron emission tomography (PET) is a fully translational imaging technology, which will help us understand the role of HO-1 in the progression of AD, facilitating to validate promising HO-1 inhibitors in clinical trials. To our knowledge, there is no report on PET imaging probe targeting HO-1 in animals and humans. We report herein the synthesis and characterization of a 11C-labeled imidazole-based alcohol derivative ([11C]QC-33) for imaging of HO-1 in the brain. The desired product [11C]QC-33 was afforded with a radiochemical yield of 16 ± 9% (n = 3, decay corrected). The radiochemical purity was greater than 99%, and the molar radioactivity was greater than 185 GBq/µmol. In vitro autoradiography studies indicated specific binding of [11C]QC-33 in the HO-1 rich regions, showing 75%, 75%, and 69% radioactivity binding reductions in cerebellum, brain stem, and midbrain, respectively. PET/CT scanning in C57BL/6 mice showed low brain uptake and poor blood-brain barrier (BBB) penetration of [11C]QC-33. These results suggested that [11C]QC-33 can serve as a lead compound to advance the development of next generation PET tracer with the potential to monitor HO-1 in AD progression.

Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging.

The orexin receptors (OXRs) have been involved in multiple physiological and neuropsychiatric functions. Identification of PET imaging probes specifically targeting OXRs enables us to better understand the OX system. Seltorexant (JNJ-42847922) is a potent OX2R antagonist with the potential to be an OX2R PET imaging probe. Here, we describe the synthesis and characterization of [18F]Seltorexant as an OX2R PET probe. The ex vivo autoradiography studies indicated the good binding specificity of [18F]Seltorexant. In vivo PET imaging of [18F]Seltorexant in rodents showed suitable BBB penetration with the highest brain uptake of %ID/cc = 3.4 at 2 min post-injection in mice. The regional brain biodistribution analysis and blocking studies showed that [18F]Seltorexant had good binding selectivity and specificity. However, pretreatment with unlabelled Seltorexant and P-gp competitor CsA observed significantly increased brain uptake of [18F]Seltorexant, indicating [18F]Seltorexant could interact P-gp at the blood-brain barrier. Our findings demonstrated that [18F]Seltorexant is a potential brain OX2R PET imaging probe, which paves the way for new OX2R PET probes development and OX system investigation.

Three-Dimensional Covalent Organic Framework with ceq Topology.

Three-dimensional covalent organic frameworks (3D-COFs) are emerging as designable porous materials because of their unique structural characteristics and porous features. However, because of the lack of 3D organic building units and the less reversible covalent bonds, the topologies of 3D-COFs to date have been limited to dia, ctn, ffc, bor, rra, srs, pts, lon, stp, acs, tbo, bcu, and fjh. Here we report a 3D-COF with the ceq topology utilizing a D3h-symmetric triangular prism vertex with a planar triangular linker. The as-synthesized COF displays a twofold-interpenetrated structure with a Brunauer-Emmett-Teller surface area of 1148.6 m2 g-1. Gas sorption measurements revealed that 3D-ceq-COF could efficiently absorb CO2, CH4, and H2 under a moderate surface area. This work provides new building units and approaches for structural and application exploration of 3D-COFs.

Imaging assisted evaluation of antitumor efficacy of a new histone deacetylase inhibitor in the castration-resistant prostate cancer.

PURPOSE: Castration-resistant prostate cancer (CRPC) is the most common cause of death in men. The effectiveness of HDAC inhibitors has been demonstrated by preclinical models, but not in clinical studies, probably due to the ineffectively accumulation of HDACI in prostate cancer cells. The purpose of this work was to evaluate effects of a novel HDACI (CN133) on CRPC xenograft model and 22Rv1 cells, and develops methods, PET/CT imaging, to detect the therapeutic effects of CN133 on this cancer. METHODS: We designed and performed study to compare the effects of CN133 with SAHA on the 22Rv1 xenograft model and 22Rv1 cells. Using PET/CT imaging with [11C] Martinostat and [18F] FDG, we imaged mice bearing 22Rv1 xenografts before and after 21-day treatment with placebo and CN133 (1 mg/kg), and uptake on pre-treatment and post-treatment imaging was measured. The anti-tumor mechanisms of CN133 were investigated by qPCR, western blot, and ChIP-qPCR. RESULTS: Our data showed that the CN133 treatment led to a 50% reduction of tumor volume compared to the placebo that was more efficacious than SAHA treatment in this preclinical model. [11C] Martinostat PET imaging could identify early lesions of prostate cancer and can also be used to monitor the therapeutic effect of CN133 in CRPC. Using pharmacological approaches, we demonstrated that effects of CN133 showed almost 100-fold efficacy than SAHA treatment in the experiment of cell proliferation, invasion, and migration. The anti-tumor mechanisms of CN133 were due to the inhibition of AR signaling pathway activity by decreased HDAC 2 and 3 protein expressions. CONCLUSION: Taken together, these studies provide not only a novel epigenetic approach for prostate cancer therapy but also offering a potential tool, [11C] Martinostat PET/CT imaging, to detect the early phase of prostate cancer and monitor therapeutic effect of CN133. These results will likely lead to human trials in the future.

Discovery of carbon-11 labeled sulfonamide derivative: A PET tracer for imaging brain NLRP3 inflammasome.

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [11C]1 exhibited rapid blood-brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [11C]1, thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains.

Research on Beers Criteria and STOPP/START Criteria based on the FDA FAERS database.

PURPOSE: Inappropriate medication criteria for the elderly have played an important role in ensuring the safety of medications for the elderly. Too few drugs included in the criteria cannot guarantee the safety of medication for the elderly. Too many drugs included in the criteria will result in less selective medication for the elderly. This paper uses real-world data to evaluate the relationship between antihypertensive drugs and falls, so as to provide references for experts and scholars to revise the criteria of potentially inappropriate medications for the elderly and clinical safe medication. METHOD: We use the US Food and Drug Administration Adverse Event Reporting System (FDA FAERS) to evaluate the association between specific antihypertensive drugs in six categories (alpha-1 receptor blockers (α-1 blockers), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-receptor blockers (ß-blockers), and diuretics) and falls by data mining algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), Medicines and Healthcare Products Regulatory Agency (MHRA), and the empirical Bayes geometric mean (EBGM) and compared with the relevant drugs included in the Beers Criteria and STOPP/START Criteria. RESULT: There are a total of 5,157,172 co-occurrences found in 973,447 reports aged 65 years or older from 2016 to 2019 in the FDA FAERS database, and the number of co-occurrences of falls is 5917 for the six categories of 51 antihypertensive drugs. Four kinds of mining methods overlap detection of 12 kinds of positive signal drugs, none of which are not included in the Beers Criteria and 7 drugs are included in the STOPP/START Criteria; 1-3 kinds of mining methods overlap detection of positive signal drugs, a total of 12 kinds, and one drug is included in the Beers Criteria and 5 drugs are included in the STOPP/START Criteria; 22 drugs have fall adverse events, but no positive signal is detected, and 13 drugs are included in STOPP/START Criteria; and 5 drugs have no fall adverse events and 3 drugs are included in the STOPP/START Criteria. CONCLUSION: The FAERS database was used to confirm the potential connection between some antihypertensive drugs and fall adverse events through data mining algorithms. The Beers Criteria did not clearly indicate the antihypertensive drugs that caused falls, and the antihypertensive drugs included in the STOPP/START Criteria were too extensive and did not include ß-blockers and diuretics. It is recommended that experts and scholars use real-world data (such as FAERS, EudraVigilance, WHO VigiBase, and so on) to further explore the relationship between specific antihypertensive drugs and falls in the elderly, so as to revise and improve the criteria for inappropriate medications for the elderly.

Molecular imaging of NAD+ -dependent deacetylase SIRT1 in the brain.

INTRODUCTION: Aging is an inevitable physiological process and the biggest risk factor of Alzheimer's disease (AD). Developing an imaging tracer to visualize aging-related changes in the brain may provide a useful biomarker in elucidating neuroanatomical mechanisms of AD. METHODS: We developed and characterized a new tracer that can be used to visualize SIRT1 in brains related to aging and AD by positron emission tomography imaging. RESULTS: The SIRT1 tracer displayed desirable brain uptake and selectivity, as well as stable metabolism and proper kinetics and distribution in rodent and nonhuman primate brains. This new tracer was further validated by visualizing SIRT1 in brains of AD transgenic mice, compared to nontransgenic animals. DISCUSSION: Our SIRT1 tracer not only enables, for the first time, the demonstration of SIRT1 in animal brains, but also allows visualization and recapitulation of AD-related SIRT1 neuropathological changes in animal brains.

[Study on medication regularity of chronic atrophic gastritis in Beijing-Tianjin-Hebei region based on latent structure model].

To explore the etiology, pathogenesis, distribution of syndromes and the rule of medication of chronic atrophic gastritis(CAG) in Beijing-Tianjin-Hebei region based on the latent structure model. Chronic atrophic gastritis of 279 cases in Beijing-Tianjin-Hebei region were extracted from the established database of spleen and stomach diseases of famous veteran Chinese medicine experts. The latent structure models of symptoms and drugs of chronic atrophic gastritis were constructed by using Lantern 3.1.2 software, and the latent structure models were interpreted. SAS 10.0 software was used to mine association rules of drugs and symptoms. The constitutional characteristics of patients with chronic atrophic gastritis in Beijing-Tianjin-Hebei region were "turbid toxin and damaging Yin". The common syndromes were turbid toxin, deficiency of stomach Yin, stagnation of liver and stomach, stagnation of liver and stomach Qi, obstruction of stomach collaterals and blood stasis, and weakness of spleen and stomach. Common medicines are Lobeliae Chinensis Herba, Scutellariae Barbatae Herba, Amomi Fructus Rotundus, Amomi Fructus, Poria, Isatidis Radix, Artemisiae Scopariae Herba, Scorpio, Coptidis Rhizoma, Lilii Bulbus, Linderae Radix, Phragmitis Rhizoma, Ophiopogonis Radix, Pogostemonis Herba, Eupatorii Herba, Magnoliae Officinalis Cortex, Aurantii Fructus Immaturus. Common prescriptions are Baihe Wuyao Powder, Danggui Shaoyao Powder, Xiaoyao Pills, Xiangsu Powder, Dachengqi Decoction, Zuojin Pills, Qingzhong Decoction, Zhishi Daozhi Pills, etc. The application of latent structure model and correlation analysis in the empirical study of famous and veteran Chinese medicine experts is in line with the research direction of modern Chinese medicine "traditional Chinese medicine + X". The conclusions obtained effectively tap the experience of famous and veteran TCM experts, and provide a data and visual clinical reference and prescription compatibility for young TCM physicians in the treatment of chronic atrophic gastritis based on syndrome differentiation.

Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.

A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.

Regioselective Access to 3-Aryl-1-aminoisoquinolines via Nickel(I)-Catalyzed C-C and C-N Cascade Coupling Reactions from the Substituted 2-(Cyanomethyl)benzonitriles.

A novel and regioselective Ni(I) catalyzed C-C and C-N cascade coupling reactions has been developed. The cascade furnishes atom-economic access to 40 3-aryl-1-aminoisoquinolines. The regioselectivity of C(sp3)-cyano group over C(sp2)-cyano group was revealed and supported by mechanism studies as well as the preliminary density functional theory (DFT) calculations.

Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib.

A series of structurally novel proteasome inhibitors 1-12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.

Synthetic access to isoxazoline-functionalized isoquinolines via microwave-assisted iminoxyl radical-participated cascade cyclization of vinyl isocyanides.

A convenient microwave-assisted method for the synthesis of isoxazoline-functionalized isoquinolines via the n-Bu4NI (TBAI) catalyzed radical cascade cyclization of vinyl isocyanides with ß,γ-unsaturated ketoximes has been described. The methodology presented here achieves a wide substrate scope and good to excellent yields. A radical mechanism is proposed, which is supported by the intermolecular competing kinetic isotope effect (KIE) experiment and the radical trapping experiment.

Microwave-assisted synthesis of hydroxyl-containing isoquinolines by metal-free radical cyclization of vinyl isocyanides with alcohols.

A convenient microwave-assisted protocol for the synthesis of hydroxyl-containing isoquinolines from a metal-free radical cyclization reaction of vinyl isonitriles with alcohols was developed with moderate-to-excellent yields. Vinyl isonitriles are coupled with alkyl radicals through direct catalytic functionalization of the α sp3 C-H bond of alcohols. The methodology demonstrates a broad substrate scope, shows excellent functional group tolerance, is highly atom-economical and highly efficient, thus enabling the preparation of diverse potentially valuable hydroxyl-containing isoquinolines.