Recent contributions of pyridazine as a privileged scaffold of anticancer agents in medicinal chemistry: An updated review.

Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

Design and synthesis of TH19P01-Camptothecin based hybrid peptides inducing effective anticancer responses on sortilin positive cancer cells.

Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.

MXene-Polydopamine-antiCEACAM1 Antibody Complex as a Strategy for Targeted Ablation of Melanoma.

Photothermal therapy (PTT) is a method for eradicating tumor tissues through the use of photothermal materials and photosensitizing agents that absorb light energy from laser sources and convert it into heat, which selectively targets and destroys cancer cells while sparing healthy tissue. MXenes have been intensively investigated as photosensitizing agents for PTT. However, achieving the selectivity of MXenes to the tumor cells remains a challenge. Specific antibodies (Ab) against tumor antigens can achieve homing of the photosensitizing agents toward tumor cells, but their immobilization on MXene received little attention. Here, we offer a strategy for the selective ablation of melanoma cells using MXene-polydopamine-antiCEACAM1 Ab complexes. We coated Ti3C2Tx MXene with polydopamine (PDA), a natural compound that attaches Ab to the MXene surface, followed by conjugation with an anti-CEACAM1 Ab. Our experiments confirm the biocompatibility of the Ti3C2Tx-PDA and Ti3C2Tx-PDA-antiCEACAM1 Ab complexes across various cell types. We also established a protocol for the selective ablation of CEACAM1-positive melanoma cells using near-infrared irradiation. The obtained complexes exhibit high selectivity and efficiency in targeting and eliminating CEACAM1-positive melanoma cells while sparing CEACAM1-negative cells. These results demonstrate the potential of MXene-PDA-Ab complexes for cancer therapy. They underline the critical role of targeted therapies in oncology, offering a promising avenue for the precise and safe treatment of melanoma and possibly other cancers characterized by specific biomarkers. Future research will aim to refine these complexes for clinical use, paving the way for new strategies for cancer treatment.

Heat shock protein (Hsp27)-ceramide synthase (Cers1) protein-protein interactions provide a new avenue for unexplored anti-cancer mechanism and therapy.

Hsp27 is a member of the small heat-shock proteins (sHSPs) - the known cellular line of defence against abnormal protein folding behaviors. Nevertheless, its upregulation is linked to a variety of pathological disorders, including several types of cancers. The ceramide synthases (CerS) mediate the synthesis of ceramide, a critical structural and signaling lipid. Functionally, downstream ceramide metabolites are implicated in the apoptosis process and their abnormal functionality has been linked to anticancer resistance. Studies showed that CerS1 are possibly inhibited by Hsp27 leading to biochemical anticancer effects in vitro. Nevertheless, the nature of such protein-protein interaction (PPI) has not been considerably investigated in molecular terms, hence, we present the first description of the dynamics CerS1-Hsp27 interaction landscapes using molecular dynamics simulations. Time-scale molecular dynamics simulation analysis indicated a system-wide conformational events of decreased stability, increased flexibility, reduced compactness, and decreased folding of CerS1. Analysis of binding energy showed a favorable interaction entailing 56 residues at the interface and a total stabilizing energy of -158 KJ/mol. The CerS1 catalytic domain experienced an opposite trend compared to the protein backbone. Yet, these residues adopted a highly compact conformation as per DCCM and DSSP analysis. Furthermore, conserved residues (SER 212, ASP 213, ALA 240, GLY 243, ASP 319) comprising the substrate shuttling machinery showed notable rigidity implying a restrained ceramide precursor access and assembly; hence, a possible inhibitory mechanism. Findings from this report would streamline a better molecular understanding of CerS1-Hsp27 interactions and decipher its potential avenue toward unexplored anti-cancer mechanisms and therapy.

Exploring the Cytotoxic and Anticancer Potential of Naringin on Oral Cancer Cell Line.

Introduction Oral cancer is the most persistent, aggressive primary malignant sarcoma that is globally prevalent. Though chemotherapy is the only treatment option, it has not progressed for years to overcome its detrimental side effects. Introducing novel therapeutic techniques to improve effectiveness is the need of the hour. Aim This study aimed to investigate the pro-apoptotic effects of naringin in oral cancer cell lines. Methodology The cell viability of oral cancer cells treated with naringin was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Naringin was given to oral cancer cells (KB-1) in concentrations ranging from 20 to 200 µM/mL for 24 hours. A phase-contrast microscope is used to examine cell morphology changes. Ethidium bromide (EtBr) staining was employed to study nuclear morphological alterations in oral cancer cells. The apoptotic nuclei were viewed under a fluorescent microscope. To determine pro-apoptotic levels, quantitative real-time polymerase chain reaction (PCR) gene expression analysis was performed to evaluate the expression of transforming growth factor-beta (TGF-ß), suppressor of mothers against decapentaplegic 2 (SMAD2), tumor necrosis factor alpha (TNFα), and nuclear factor kappa B (NFκB). A scratch wound healing experiment was used to evaluate naringin's anti-migratory properties. Results Our study found that naringin treatment significantly reduced cell viability in oral cancer cells compared to the control group (p < 0.05). In oral cancer cells, we found an inhibitory concentration (IC50) of 125.3 µM/mL. Following treatment, fewer cells were present, and those that were present shrunk and displayed cytoplasmic membrane blebbing. The EtBr staining reveals chromatin condensation and nuclear breakage in treated cells. The study found that naringin downregulates the expression of B-cell leukemia/lymphoma 2 (Bcl-2), TGF-ß, SMAD2, TNFα, and NFκB and upregulates the expression of Bcl-2-associated agonist of cell death (BAD), Bcl-2-associated protein X (BAX), and caspase-3. Furthermore, when compared to control cells, naringin significantly reduced cell migration. Naringin treatment significantly promotes apoptosis and inhibits migration by altering the SMAD2 signaling pathway. Conclusion Overall, this study highlights the promising role of naringin as a pro-apoptotic and cytotoxic phytochemical regulating the gene expression of Bcl-2, TGF-ß, SMAD2, TNFα, NFκB, BAD, BAX, and caspase-3, thereby treating oral cancer.

Mitigating Cardiotoxicity Associated with Anticancer Drugs: An Updated Systematic Review.

Introduction: This systematic review investigated strategies to mitigate cardiotoxicity induced by anticancer medications, emphasizing exercise and pharmacological interventions. Methods: We systematically reviewed three randomized controlled trials, one ATOPE trial, and one retrospective cohort study. Results: Among 448 patients, exercise interventions, particularly in breast cancer patients, demonstrated significant improvements in left ventricular ejection fraction (LVEF) and cardiotoxicity prevention. Pharmacological interventions, including candesartan and carvedilol, have shown potential in reducing early DOX-induced subclinical cardiotoxicity (DISC). The protective efficacy of candesartan in alleviating DISC was greater than carvedilol and the control group. Combination therapy with lisinopril and bisoprolol effectively preserved the LVEF. A retrospective cohort study demonstrated the cardioprotective potential of sodium-glucose cotransporter-2 inhibitors in reducing cardiovascular events. Conclusion: This systematic review underscores the promise of exercise and pharmacological interventions for preserving cardiac function in cancer patients receiving chemotherapy. These findings have significant implications for enhancing the quality of care for cancer patients.

Production and bioprocessing of epothilone B from Aspergillus niger, an endophyte of Latania loddegesii, with a conceivable biosynthetic stability: anticancer, anti-wound healing activities and cell cycle analysis.

Epothilones are one of the common prescribed anticancer drugs for solid tumors, for their exceptional binding affinity with ß-tubulin microtubule, stabilizing their disassembly, causing an ultimate arrest to the cellular growth. Epothilones were initially isolated from Sornagium cellulosum, however, their extremely slow growth rate and low yield of epothilone is the challenge. So, screening for a novel fungal endophyte dwelling medicinal plants, with higher epothilone productivity and feasibility of growth manipulation was the objective. Aspergillus niger EFBL-SR OR342867, an endophyte of Latania loddegesii, has been recognized as the heady epothilone producer (140.2 µg/L). The chemical structural identity of the TLC-purified putative sample of A. niger was resolved from the HPLC, FTIR and LC-ESI-MS/MS analyses, with an identical molecular structure of the authentic epothilone B. The purified A. niger epothilone B showed a resilient activity against MCF-7 (0.022 µM), HepG-2 (0.037 µM), and HCT-116 (0.12 µM), with selectivity indices 21.8, 12.9 and 4, respectively. The purified epothilone B exhibited a potential anti-wound healing activity to HepG-2 and MCF-7 cells by ~ 54.07 and 60.0%, respectively, after 24 h, compared to the untreated cells. The purified epothilone has a significant antiproliferative effect by arresting the cellular growth of MCF-7 at G2/M phase by ~ 2.1 folds, inducing the total apoptosis by ~ 12.2 folds, normalized to the control cells. The epothilone B productivity by A. niger was optimized by the response surface methodology, with ~ 1.4 fold increments (266.9 µg/L), over the control. The epothilone productivity by A. niger was reduced by ~ 2.4 folds by 6 months storage as a slope culture at 4 °C, however, the epothilone productivity was slightly restored with ethylacetate extracts of L. loddegesii, confirming the plant-derived chemical signals that partially triggers the biosynthetic genes of A. niger epothilones. So, this is the first report emphasizing the metabolic potency of A. niger, an endophyte of L. loddegesii, to produce epothilone B, that could be a new platform for industrial production of this drug.

Bidentate bromhexine drug coordination modes with various transition metal ions: Synthesis, characterization, and in vitro antibacterial and anti-breast cancer activity tests.

BACKGROUND: Bromhexine (BHX) is a mucolytic drug used in treatment the respiratory disorders which are associated with excessive or viscid mucus. Transition metal complexes have made tremendous progress in the treatment of a variety of human ailments, according to reported articles. Transition metal complexes are being developed as medications with a lot of effort. Metal complexes can form a variety of coordination geometries, giving them distinct forms. So, binary metal complexes of bromhexine drug have been prepared to enhance the biological activity and stability of the free drug. METHODS: A new series of binary complexes with bromhexine drug (BHX) has been prepared with some transition metal ions namely Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II). Elemental analyses, FT-IR, mass spectrometry, thermal studies and UV-Vis spectra have been used to characterize and structurally elucidate the produced metal complexes. Antibacterial activity has been tested for the ligand and metal complexes against a variety of pathogenic bacterial species (Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus). In addition, the ligand has been tested for anticancer efficacy against the MCF-7 breast cancer cell line, as opposed to binary metal complexes. The binding orientation or conformation of the free BHX ligand and Co(II) complex in the active region of the protein of crystal structure of Escherichia coli (PDB ID: 3T88) and Pseudomonas aeruginosa (PDB ID: 6NE0) has been performed using molecular docking studies. RESULTS: The BHX ligand coupled in neutral bidentate mode to the metal ions, according to FT-IR and 1H-NMR spectral results. The molar conductivity measurements of the complexes in DMF proved the electrolytic nature of all binary complexes. Co(II) complex showed the highest inhibition zone diameter against S. aureus, E. coli and P. aeruginosa. Zn(II) complex had the greatest inhibitory effect against P. aeruginosa and B. subtilis. Also, Cd(II) chelate appeared high efficacy as antibacterial agent against Pseudomonas aeruginosa and Staphylococcus aureus. CONCLUSION: All the output data conjugated to confirm the octahedral geometry of the metal complexes. The biological findings revealed that metal complexes can be more active than the free BHX ligand. Against MCF-7 cell line, Cd(II)-L complex is highly active complex (4.95 µg/mL) but BHX free drug is the most active compound (3.96 µg/mL).

Synthesis, biological activities and mechanistic studies of C20-ketone pachysandra alkaloids as anti-hepatocellular carcinoma agents.

The pachysandra alkaloids found in Sarcococca ruscifolia demonstrate notable anti-hepatocellular carcinoma activity. Despite their efficacy, the structural diversity of these compounds remains limited, and their precise antitumor mechanism is still unclear. In pursuit of identifying novel lead compounds with high efficacy and low toxicity for combating hepatocellular carcinoma, twenty-three compounds of C20-ketone pachysandra alkaloid derivatives were designed and synthesized by using 3-dimethylamine pachysandra alkaloids as scaffolds. Subsequent in vitro anticancer activity experiments showed that synthetic pachysandra alkaloids had a stronger effect on HepG2 cells than did their natural counterparts, with low toxicity and high selectivity. The most potent derivative, 6k, had an IC50 value of 0.75 µM, demonstrating 25.7-fold greater anticancer activity than sarcovagine D against HepG2 cells. Through network pharmacology and molecular docking analysis, it was revealed that synthetic pachysandra alkaloids may exert their effects by inhibiting the JAK2/STAT3 pathway, thereby preventing the proliferation of liver cancer cells. Further research through scratch tests, immunofluorescence experiments, and Western blot analysis revealed that compound 6k effectively inhibited the migration of HepG2 cells and induced mitochondria-mediated intrinsic apoptosis of HepG2 cells by regulating the JAK2/STAT3 signaling pathway. The aforementioned results indicate that compound 6k could be developed as a potential candidate for the treatment of hepatocellular carcinoma.

A review of the ethnomedicinal, phytochemical, and pharmacological properties of the Ferulago genus based on Structure-Activity Relationship (SAR) of coumarins.

BACKGROUND: The Ferluago W.D.J. Koch genus includes 48 accepted perennial herbs that are distributed in the Mediterranean region, Southeast Europe, Central and Middle East of Asia. These plants are widely used in folk and conventional medicine due to their biological benefits such as anti-microbial, anti-inflammatory, anti-cancer, and immunomodulatory properties. Conducting a comprehensive review based on the structure activity relationships (SARs) of the coumarins, which has not been previously documented, can lead to a better insight into the genus Ferulago and its beneficial therapeutic activities. METHODS: This review covers literature from 1969 to 2023, were collected from various scientific electronic databases to review phytochemical, pharmacological, and ethnopharmacological data of Ferulago species, as well as latest information on the SAR of reported coumarins from this genus. RESULTS: Phytochemical studies showed that the biological actions of this genus are mediated by the reported specialized metabolites, such as coumarins and flavonoids. Simple coumarins, prenylated coumarins, furanocoumarins, and pyranocoumarins are the largest subclasses of coumarins found in diverse Ferulago species, which have discussed the biological effects of them with a focus on the Structure-Activity Relationship (SAR). For example, prenylated coumarins have shown potential leishmanicidal and anti-neuropsychiatric effects when substituted with a prenyl group at the 7-hydroxy, as well as the C6 and C8 positions in their scaffold. Similarly, furanocoumarins exhibit varied biological activities such as anti-inflammatory, anti-proliferative, and anti-convulsant effects. Modifying substitutions at the C5 and C6 positions in furanocoumarins can enhance these activities. CONCLUSION: This study conducted a comprehensive review of all available information on the phytochemical and pharmacological characteristics of Ferulago species. Given the high occurrence of coumarins in this genus, which exhibit potential anti-Alzheimer and anti-microbial properties, it presents promising new therapeutic avenues for addressing these common issues. Further investigation is needed to understand the molecular-level mechanisms of action and to explore their clinical applications.

Serum Biomarkers to Dynamically Predict the Risk of Cardiovascular Events in Patients under Oncologic Therapy. A Multicenter Observational Study.

Background: Serum biomarkers have been investigated as predictive risk factors for cancer-related cardiovascular (CV) risk, but their analysis is limited to their baseline level rather than their overtime change. Besides historically validated causal factors, inflammatory and oxidative stress (OS) related markers seem to be correlated to CV events but this association needs to be further explored. We conducted an observational study to determine the predictive role of the longitudinal changes of commonly used and OS-related biomarkers during the cancer treatment period. Methods: Patients undergoing anticancer therapies, either aged 75+ years old or younger with an increased CV risk according to European Society of Cardiology guidelines, were enrolled. We assessed the predictive value of biomarkers for the onset of CV events at baseline and during therapy using Cox model, Subpopulation Treatment-Effect Pattern Plot (STEPP) method and repeated measures analysis of longitudinal data. Results: From April 2018 to August 2021, 182 subjects were enrolled, of whom 168 were evaluable. Twenty-eight CV events were recorded after a median follow up of 9.2 months (Interquartile range, IQR: 5.1-14.7). Fibrinogen and troponin levels were independent risk factors for CV events. Specifically, patients with higher than the median levels of fibrinogen and troponin at baseline had higher risk compared with patients with values below the medians, hazard ratio (HR) = 3.95, 95% CI, 1.25-12.45 and HR = 2.48, 0.67-9.25, respectively. STEPP analysis applied to Cox model showed that cumulative event-free survival at 18 and 24 months worsened almost linearly as median values of fibrinogen increased. Repeated measure analysis showed an increase over time of D-Dimer (p-interaction event*time = 0.08), systolic (p = 0.07) and diastolic (p = 0.05) blood pressure and a decrease of left ventricular ejection fraction (p = 0.15) for subjects who experienced a CV event. Conclusions: Higher levels of fibrinogen and troponin at baseline and an increase over time of D-Dimer and blood pressure are associated to a higher risk of CV events in patients undergoing anticancer therapies. The role of OS in fibrinogen increase and the longitudinal monitoring of D-dimer and blood pressure levels should be further assessed.

Design, synthesis and biological evaluation of multitarget hybrid molecules containing NHC-Au(I) complexes and carbazole moieties.

N-heterocyclic carbenes (NHCs) represent suitable ligands for rapid and efficient drug design, because they offer the advantage of being easily chemically modified and can bind several substituents, including transition metals as, for instance, gold derivatives. Gold-NHC complexes possess various biological activities and were demonstrated good candidates as anticancer drugs. Besides, carbazole derivatives are characterized by various pharmacological properties, such as anticancer, antibacterial, anti-inflammatory, and anti-psychotropic. Amongst the latter, N-thioalkyl carbazoles were proved to inhibit cancer cells damaging the nuclear DNA, through the inhibition of human topoisomerases. Herein, we report the design, synthesis and biological evaluation of nine new hybrid molecules in which NHC-Au(I) complexes and N-alkylthiolated carbazoles are linked together, in order to obtain novel biological multitarget agents. We demonstrated that the lead hybrid complexes possess anticancer, anti-inflammatory and antioxidant properties, with a high potential as useful tools for treating distinct aspects of several diseases, amongst them cancer.

Monodispersed Au nanoparticles decorated MoS2 nanosheets with enhanced peroxidase-like activity based electrochemical H2O2 sensing for anticancer drug evaluations.

BACKGROUND: The unique size, physical and chemical properties, and ultra-high stability of nanozymes have attracted extensive attentions in sensing, but improvement of catalytic activity of the nanozymes is still an urgent issue. Given the ultra-high simulated enzyme activity of metal nanoparticles and the advantage of multi-enzyme catalysis, an Au-decorated MoS2 nanosheets (MoS2/Au NS) integrating the double peroxidase-like (POD) activity is developed. RESULTS: By optimizing and adjusting the density of AuNPs, as well as its morphology and other parameters, a monodisperse and high-density distribution of AuNPs on MoS2 nanosheets was obtained, which can greatly improve the POD-like activity of MoS2/Au NS. Nafion solution was applied to assist the modification of MoS2/Au NS on the electrode surface so as to improved its stability. An electrochemical H2O2 detection platform was constructed by modifying MoS2/Au NS nanozyme on the SPCE using the conductive Nafion solution. And the negatively charged sulfonic acid group can eliminate negatively charged electroactive substances to improve the specificity. Then ascorbic acid was used to stimulate tumor cells to produce H2O2 as therapeutic model, an ultrasensitive chronocoulometry detection for H2O2 in cell lysate was established. The logarithmically of ΔQ and the logarithmically of H2O2 concentration showed a good linear relationship between 1 µM and 500 mM, with a LOD value of 0.3 µM. SIGNIFICANCE: The developed H2O2 sensor has excellent stability, reproducibility (RSD = 2.3 %, n = 6) and selectivity, realized the quantitative detection of H2O2 in cell lysate. Compared with commercial fluorescence detection kits for H2O2 in cell lysate, it is worth mentioning that the electrochemical H2O2 sensor developed in this study is simpler and faster, with higher sensitivity and lower cost. This provides a potential substitute for disease diagnosis and treatment evaluation based on accurate detection of H2O2.

Oil/water (O/W) nanoemulsions developed from essential oil extracted from wildly growing Calotropis gigantea (Linn.) Aiton F.: synthesis, characterization, stability and evaluation of anti-cancerous, anti-oxidant, anti-inflammatory and anti-diabetic activities.

Calotropis gigantea essential oil is utilized in outmoded medicine, therapeutics, and the cosmetic industries. However, the extreme volatility, oxidation susceptibility, and instability of this oil restricts its application. Thus, encapsulation is a more effective method of shielding this oil from unfavorable circumstances. The creation of oil/water (O/W) nanoemulsions based on Calotropis gigantea essential oil (CEO), known as CNE (Calotropis gigantea essential oil nanoemulsions), and an assessment of its biological potential were the goals of this work. UV, fluorescence, and FT-IR methods were used for physiological characterization. Biological activities, including anti-inflammatory, anti-diabetic, and anti-cancer effects. Studies on the pharmacokinetics of CNE were conducted. CNEs encapsulation efficiency was found to be 92%. The CNE nanoemulsions had a spherical shape with polydispersity index of 0.531, size of 200 nm, and a zeta potential of -35.9 mV. Even after being stored at various temperatures for 50 days, CNE nanoemulsions remained stable. Numerous tests were used to determine the antioxidant capacity of CNE, and the following IC50 values (µl/mL) were found: iron chelating assay: 18, hydroxyl radical scavenging: 37, and nitric oxide radical scavenging activity: 58. The percentage of HeLa cells that remained viable after being treated with CNE was 41% at a higher dose of 1 µl. CNE inhibited α-amylase in a dose-dependent manner, with 72% inhibition at its higher dose of 250 µL. Research on the kinetics of drugs showed that nanoemulsions showed Higuchi pattern. This research showed potential use of Calotropis gigantea oil-based nanoemulsions in the food, cosmetic, and pharmaceutical industries.

A narrative review and new insights into the protective effects of taurine against drug side effects.

Taurine, a non-essential amino acid produced from cysteine, is abundant in body tissues and blood plasma. It plays vital roles in growth, osmosis, lipid metabolism, and neurohormonal modulation. Taurine has antioxidant, anti-apoptotic, and anti-inflammatory properties, and its deficiency can lead to various diseases including cardiovascular, diabetic, renal, and liver disorders. This report provides a comprehensive review of the functional properties of taurine in counteracting pharmaceutical-induced side effects. A search across databases such as Scopus, PubMed, MEDLINE, and Web of Science yielded 109 articles, of which 75 were included in the study. These results suggest that the protective effects of taurine involve mechanisms such as influencing pathways of Nrf2/OH-1, PI3-kinase/AKT and ERK2, boosting antioxidants (SOD, GPx and CAT), and suppression of inflammatory cytokines (TNF-α, IL-1ß and IL-6). Overall, supplementation with taurine along with medications with significant side effects may mitigate these effects and enhance their efficacy. Further investigation of the interactions between taurine and other nutrients or compounds may provide insights into synergistic effects and novel therapeutic approaches.

Inhibition of human DNA alkylation damage repair enzyme ALKBH2 by HIV protease inhibitor ritonavir.

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA and is overexpressed in several cancers. However, there are no known inhibitors available for this crucial DNA repair enzyme. The aim of this study was to examine whether the first-generation HIV protease inhibitors having strong anti-cancer activity can be repurposed as inhibitors of ALKBH2. We selected four such inhibitors and performed in vitro binding analysis against ALKBH2 based on alterations of its intrinsic tryptophan fluorescence and differential scanning fluorimetry. The effect of these HIV protease inhibitors on the DNA repair activity of ALKBH2 was also evaluated. Interestingly, we observed that one of the inhibitors, ritonavir, could inhibit ALKBH2-mediated DNA repair significantly via competitive inhibition and sensitized cancer cells to alkylating agent methylmethane sulfonate (MMS). This work may provide new insights into the possibilities of utilizing HIV protease inhibitor ritonavir as a DNA repair antagonist.

Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

Efficient prediction of anticancer peptides through deep learning.

Background: Cancer remains one of the leading causes of mortality globally, with conventional chemotherapy often resulting in severe side effects and limited effectiveness. Recent advancements in bioinformatics and machine learning, particularly deep learning, offer promising new avenues for cancer treatment through the prediction and identification of anticancer peptides. Objective: This study aimed to develop and evaluate a deep learning model utilizing a two-dimensional convolutional neural network (2D CNN) to enhance the prediction accuracy of anticancer peptides, addressing the complexities and limitations of current prediction methods. Methods: A diverse dataset of peptide sequences with annotated anticancer activity labels was compiled from various public databases and experimental studies. The sequences were preprocessed and encoded using one-hot encoding and additional physicochemical properties. The 2D CNN model was trained and optimized using this dataset, with performance evaluated through metrics such as accuracy, precision, recall, F1-score, and area under the receiver operating characteristic curve (AUC-ROC). Results: The proposed 2D CNN model achieved superior performance compared to existing methods, with an accuracy of 0.87, precision of 0.85, recall of 0.89, F1-score of 0.87, and an AUC-ROC value of 0.91. These results indicate the model's effectiveness in accurately predicting anticancer peptides and capturing intricate spatial patterns within peptide sequences. Conclusion: The findings demonstrate the potential of deep learning, specifically 2D CNNs, in advancing the prediction of anticancer peptides. The proposed model significantly improves prediction accuracy, offering a valuable tool for identifying effective peptide candidates for cancer treatment. Future Work: Further research should focus on expanding the dataset, exploring alternative deep learning architectures, and validating the model's predictions through experimental studies. Efforts should also aim at optimizing computational efficiency and translating these predictions into clinical applications.

Moscatilin, a potential therapeutic agent for cancer treatment: insights into molecular mechanisms and clinical prospects.

Moscatilin, a bibenzyl derivative from the Dendrobium genus, has been traditionally used in Chinese medicine. Recent studies suggest its potential as a powerful anticancer agent due to its diverse pharmacological properties.This review aims to consolidate current research on moscatilin's anticancer mechanisms, structure-activity relationships, and therapeutic potential to assess its viability for clinical use. A literature search was performed in PubMed/MedLine, Scopus, and Web of Science.The search focused on "cancer," "moscatilin," "anticancer," "bioactivity," "dendrobium," and "pharmacological properties." Relevant studies on molecular mechanisms, preclinical and clinical efficacy, and bioavailability were reviewed. Moscatilin exhibits significant anticancer effects in lung, breast, colorectal, and pancreatic cancers. It induces apoptosis via the JNK/SAPK pathway, inhibits cell proliferation, and suppresses metastasis. Structure-activity relationship studies reveal that phenolic groups and a two-carbon bridge are crucial for its efficacy. Additionally, moscatilin shows good bioavailability and a favorable safety profile, with low toxicity to healthy cells. Moscatilin demonstrates considerable potential as an anticancer agent, targeting multiple cancer progression pathways. Further clinical trials are essential to confirm its therapeutic efficacy and safety in humans.

The Investigation of Hsp90 C-terminal inhibitors containing Amide bioisosteres.

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti-proliferative activity manifested by a series of Hsp90 C-terminal inhibitors against mutant BRAF and wild-type BRAF melanoma cells. Furthermore, we explored structure-activity relationships (SAR) for the amide moiety of 6 (B1), a novel Hsp90 C-terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC50 of 1.01 µM, 0.782 µM, 0.607 µM and 1.413 µM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively.