Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with genetic predispositions such as Familial Adenomatous Polyposis (FAP) contributing significantly to early-onset disease. This study investigated the synergic chemopreventive potential of two non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA) and sulindac (SU), in combination with a pesco-vegetarian diet (PVD), using Apc-mutated PIRC rats, a well-established model of CRC. Animals were treated over three months with two doses of ASA (800 and 1600 ppm) or a single low dose of SU (80 ppm), and tumour burden and gut microbiota composition were assessed. Results confirmed the robust protective effect of the PVD diet in reducing the intestinal tumorigenesis, particularly in the colon, independent of pharmacological treatment. ASA treatment, especially at the higher dose, significantly reduced tumour incidence in both dietary groups, with additive effects seen in combination with PVD, while SU did not show a significant protective effect. Microbiota analysis revealed distinct shifts in bacterial composition associated with both dietary and pharmacological interventions. Notably, taxa such as Roseburia and Colidextribacter, previously linked to intestinal homeostasis and anti-inflammatory activity, were modulated by ASA and diet, suggesting a microbiome-mediated chemoprevention although mechanistic effect still need to be understood. These findings underscore the independent and complementary roles of diet and pharmacological interventions in CRC prevention and highlight the gut microbiota as a promising target for future personalised preventive strategies.

Catalytic carboxylation of ubiquitous C─H bonds with CO2 has been demonstrated as a sustainable and streamlined pathway to valuable carboxylic acids. However, the catalytic carboxylation of abundant allylic C(sp[3])─H bonds with CO2, which presents a unique opportunity to synthesize structurally diverse 3-butenoic acids, still remains challenging. Herein, we report the first copper metallaphotoredox-catalyzed formal allylic C(sp[3])─H carboxylation with CO2, enabling efficient and selective synthesis of 3-butenoic acids under mild and redox-neutral conditions. This strategy lies in combining highly reducing photocatalysts to generate alkene radical anion intermediates with copper catalysis to orchestrate regioselective elimination, providing a distinct pathway from traditional allylic C(sp[3])─H functionalization via forming allyl-metal intermediates. This method features high atom and step economy, broad substrate scope, good functional group tolerance, facile scalability, and easy access to valuable compounds, including diverse bioactive molecules, natural products, and [13]C-labeled anti-inflammatory drug sulindac.

Up to now, most hydrogel-related studies have been devoted to the preparation of drug-containing macromolecular gels via the introduction of polymer matrices, together with the clarification of their assembly mechanisms and biomedical applications. In contrast, studies concerning the design of small-molecule gel systems remain relatively limited. As gel research progresses, drug small-molecule hydrogels have attracted growing interest for formulation development. This study investigated whether designing a small-molecule hydrogel could serve as an effective solubilization approach for sulindac (SUL)-a nonsteroidal anti-inflammatory drug clinically restricted by its poor aqueous solubility. Then, a SUL small-molecule hydrogel was prepared by straightforward mixing of SUL with biologically safe meglumine (MEG) in a minimal volume of deionized water, which exhibited a characteristic three-dimensional network structure and favorable viscoelastic properties. The characterization and simulation results indicated that the hydrogel formation was contingent upon the SUL-MEG miscibility, dissolution-aggregation equilibrium and intermolecular self-assembly. Consequently, the resulting SUL-MEG hydrogel exhibited 546 times higher solubility compared to the pure SUL. Meanwhile, the SUL-MEG hydrogel demonstrated superior release kinetics and supersaturation capacity, characterized by rapid attainment of peak concentrations and sustained supersaturated release. These enhanced performances were attributed to the high-energy state of the hydrogel itself and the molecular complexation between SUL and MEG. In conclusion, this study presents a feasible formulation strategy for overcoming the poor water solubility of insoluble drugs through the development of small-molecule hydrogel formulations.

The traditional medicinal plant Barleria buxifolia L is well-known for its pharmacological properties. This study aims to predict the binding affinity of bioactive compounds obtained from B. buxifolia towards significant molecular targets associated with diabetes mellitus. The polyol pathway enzyme aldose reductase is associated with diabetes, making it a possible therapeutic target.

The structural modification of drug molecules is a fundamental approach to optimizing lead compounds designed to achieve concurrent improvements in efficacy, pharmacokinetics, and safety. Herein, we disclose an efficient and eco-benign electrochemical oxidative protocol for regioselective and chemoselective difunctionalization of the sulindac alkene scaffold under transition-metal-free, exogenous oxidant-free, and base-free conditions. This methodology delivers diverse sulindac derivatives in moderate to excellent yields (up to 92%) with a broad functional group tolerance. Mechanistic studies reveal a radical-radical cross-coupling process, offering a novel strategy for alkene difunctionalization.

A rapid, specific, and sensitive LC-MS/MS method for the determination of sulindac and its metabolite Su-EP-C in human EDTA-K2 plasma was developed. The method was fully validated using sulindac-d3 and Su-EP-C-d3 as internal standards. Separation was performed on a Kinetex C18 analytical column (100 Å, 50 × 2.1 mm, 5 μm). MPA consisted of 0.05% formic acid (FA) in water, while MPB comprised 0.05% FA in ACN. The flow rate was maintained at 0.300 mL/min, and the injection volume was 3 μL. Mass spectrometry conditions: ESI, positive mode, MRM. The linear range of detection was from 60.00 to 24,000.00 ng/mL for sulindac and from 30.00 to 12,000.00 ng/mL for Su-EP-C. The intra- and interbatch accuracy deviations of sulindac ranged from -5.1 to 5.0%, and the intra- and interbatch precision ranged from 3.3 to 4.2%. The intra- and interbatch accuracy of Su-EP-C ranged from -3.9 to 6.9%, and the intra- and interbatch precision ranged from 4.8 to 7.2% at all concentration levels. At a dilution of 10, the deviation for sulindac was 3.5% and the precision was 1.5%; the deviation for Su-EP-C was 2.7%, and the precision was 4.4%. The plasma matrix, at both -20 °C and -70 °C, remained stable for 52 days with 5 freeze-thaw cycles. The method was successfully applied to fasting and postprandial pharmacokinetic clinical trials of orally administered sulindac tablets.

The human gut microbiome plays a crucial role in the metabolism of drugs, with various bacterial species catalysing the biotransformation of pharmaceutical compounds. In vitro microbiota models, typically derived from faecal material, have been employed to study this phenomenon. However, they often do not fully capture the complex and dynamic environment of the living colon. This study aimed to evaluate whether in vitro models accurately reflect in vivo microbiota-drug interactions by comparing both approaches within the same individual animal via a fistulated dog model, with the fistula located in the ascending colon. We investigated the metabolism of metronidazole and sulindac, two structurally and pharmacologically distinct drugs, before and after broad-spectrum antibiotic treatment. Prior to antibiotics, in vitro biotransformation in faecal material was observed for both drugs: metronidazole (t₁/₂ = 22.9 ± 1.2 min) and sulindac (t₁/₂ = 104.2 ± 1.0 min). Following antibiotic treatment, no measurable degradation occurred in vitro. However, in the fistulated dog model plasma concentrations decreased following antibiotic treatment compared to pre-treatment levels, indicating a lack of correlation between microbiota metabolism observed in vitro and systemic drug levels in vivo. These findings underscore the complexity of microbiota-host-drug interactions and provide important insights for the development of translational microbiome-pharmacology models. Additionally, the drawbacks over the use of antibiotic-treated animal models to study microbiota-drug interactions are discussed due to antibiotic-induced changes in intestinal permeability and efflux that may influence drug absorption and metabolism.

Despite numerous research efforts and several effective vaccines and therapies developed against coronavirus disease 2019 (COVID-19), drug repurposing remains an attractive alternative approach for treatment of SARS-CoV-2 variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of two polyamine metabolism-targeting drugs, an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), and a non-steroidal anti-inflammatory drug (NSAID), Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in the human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. In the infected human cell lines, the DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The Sulindac alone and DFMO/Sulindac combination treatments also suppressed the expression of the viral Spike protein and the host angiotensin-converting enzyme 2 (ACE2). In K18-hACE2 mice, the antiviral activity of DFMO and Sulindac as single agents and in combination was tested as prophylaxis (drug supplementation started 7 days before infection) or as treatment (drug supplementation started 24 h post-infection) at the doses equivalent to patient chemoprevention trials (835 ppm DFMO and 167 ppm Sulindac). The drugs' antiviral activity in vivo was evaluated by measuring the clinical (survival rates and clinical scores), viral (viral load and virus infectivity), and biochemical (plasma polyamine, Sulindac, and Sulindac metabolite levels) endpoints. Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p = 0.01 and p = 0.027, respectively), and the combination was effective in the aged male mice (p = 0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p = 0.001) and the DFMO/Sulindac combination (p = 0.018), while aged female mice did not benefit significantly from any intervention. Treatment of SARS-CoV-2-infected animals with DFMO or/and Sulindac did not significantly improve their survival rates. Overall, our studies demonstrated that DFMO and Sulindac administration as the prophylaxis regimen provided strong protection against the lethal outcome of SARS-CoV-2 infection and that male mice benefited more from the polyamine-targeted antiviral treatment than female mice. Our findings underscore the importance of evaluation of the antiviral activity of the drugs in the context of sex and age.

Chronic pain remains a massive problem in society in general, and in mental health patients in particular, being strongly bi-directionally connected to mental health. Lack of widespread use of objective information has hampered treatment and prevention efforts. Pain is a spectrum of severity, from transient vague discomfort to chronic excruciating incapacitation. Blood biomarkers that track pain severity can provide a window into the biology of pain, as well as could help with assessment and treatment. A previous study by us was positive. Here we describe new studies we conducted trans-diagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for pain. We carried out two separate studies, on two different platforms, microarrays and RNA sequencing, using for each study a multiple independent cohorts design. This ensured biological and technical reproducibility. We then focused at the end on biomarkers that were convergent and reproducible between the two studies. We found new as well as previously known biomarkers that were predictive of high pain states, and of future emergency department visits related to them, using cross-sectional and longitudinal approaches. Using a polyevidence score, the overall top decreased in expression biomarker ("pain-suppressor gene") was CD55, a gene that suppresses the complement cascade and cell damage. The top increased biomarker ("algogene") was ANXA1, a gene that is an effector of glucocorticoid-mediated responses and regulator of the inflammatory processes. The top biological pathways were related to cellular response to TNF and to neuroinflammation. The top upstream regulator was TNF. Top therapeutic matches overall were the medications lithium and ketamine, as well as the nutraceuticals omega-3 fatty acids and magnesium. Drug repurposing bioinformatic analyses also identified the potential of carvedilol, sirolimus, budesonide, berbamine, and quetiapine, as well as of medications already used to treat pain such as amyleine, sulindac, sufentanil, carbamazepine, and meclofenamic acid, that serve as de facto positive controls. Additionally, we show how personalized patient reports for doctors would look like based on blood biomarkers testing, to aid with objective assessment of severity and risk, as well with individualized matching to medications and nutraceuticals. Given the fact that pain disorders are highly prevalent, can severely affect quality of life, and even lifespan, there is an urgent need for insights and tools such as the ones we have developed to be applied to and improve clinical diagnosis, treatment, and prevention options.

A new series of cis-β-lactam derivatives was synthesized from the anti-inflammatory drugs diclofenac and sulindac via a Staudinger [2 + 2] cycloaddition of ketenes with various imines, and the exclusively formed cycloadducts were fully characterized by spectroscopic methods. All synthesized compounds were screened for antiproliferative activity against MCF-7 breast cancer cells. Among them, compound 16 proved most potent (IC50 = 21.74 µM; SI = 36.1) and was further evaluated against A375 melanoma cells (IC50 = 168.0 µM; SI = 1.2). Furthermore, the total antioxidant capacity of compounds 12, 13, and 15-17 was assessed. Molecular docking studies of the mitotic kinase TTK showed strong binding for all compounds, with compounds 16 and 17 displaying especially strong interactions in the TTK-binding pocket, supporting experimental kinase inhibition findings. Computational analyses, including DFT calculations, revealed that compounds 16 and 17 possess favorable electronic properties, with lower HOMO-LUMO gaps suggesting enhanced reactivity. ADMET predictions revealed favorable pharmacokinetic properties for all compounds, with compounds 16 and 17 exhibiting good membrane permeability, minimal toxicity aside from immunotoxicity, and adequate bioavailability. In addition, molecular dynamics simulations confirmed the structural stability and sustained binding of the 16-TTK and 17-TTK complexes under physiological conditions.

Here, we briefly discuss 17 PCT patent applications related to drug repurposing that were published during the final quarter of 2024. As always, we have chosen the documents based on significance only, which gave us a wide range of applicants, active agents, and geographic representation. Applicants are not only from the United States and China but also from Japan, Germany, the United Kingdom, Canada, and even remote places such as Algeria and Iceland. Significantly, the contribution from Iceland is how to induce therapeutic hypothermia-but with entacapone, used in Parkinson's disease. The UK company, HealX, presents data showing that Angelman syndrome, an intractable neurodevelopmental disorder, could be treated with the common NSAID sulindac. Gliclazide, an old antidiabetic, could potentially treat schizophrenia, as inventors from Chinese Ping An-Shionogi report. These are only a few highlights from the stream of documents that have been issued towards the end of 2024.