Targeting Biomolecular Condensation and Protein Aggregation against Cancer.

Biomolecular condensates, membrane-less entities arising from liquid-liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

Are there differences between patients with unifocal nummular headache and those who progress to bifocal nummular headache? A retrospective observational study.

OBJECTIVES: This retrospective observational cohort study aimed to compare clinical characteristics and treatment responses in patients exclusively experiencing unifocal nummular headache (NH) with those who develop the bifocal variant. METHODS: A retrospective study was conducted on patients diagnosed with NH who attended a neurology (headache) outpatient clinic between January 2018 and December 2022. The cohort was divided into two groups: Group 1, exclusive unifocal NH; and Group 2, those developing a secondary focal area of pain, i.e., bifocal NH. Data were collected on demographic characteristics, clinical features, other headache comorbidities, and treatment-related information. RESULTS: A total of 23 patients were included in this study: 12 were categorized as unifocal NH (Group 1) and 11 as bifocal NH (Group 2). There were no differences between the two groups in terms of demographic characteristics, clinical features, or treatment response. Nonetheless, patients with bifocal NH exhibited spontaneous remission rates in the first pain area when compared to the unifocal NH group, with statistically significant differences (36% vs. 0%, p = 0.020). CONCLUSION: In our sample, patients with bifocal NH demonstrated spontaneous remission rates in the initial pain area, a phenomenon not observed in patients with unifocal NH. It is worth noting the limited sample size in the present study, highlighting the need for larger cohorts to validate and further explore our findings.

Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Naphthoquinone-Quinolone Hybrids with Antitumor Effects on Breast Cancer Cell Lines-From the Synthesis to 3D-Cell Culture Effects.

Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.

Inclusion complex of O-allyl-lawsone with 2-hydroxypropyl-ß-cyclodextrin: Preparation, physical characterization, antiparasitic and antifungal activity.

The subclass naphthoquinone represents a substance group containing several compounds with important activities against various pathogenic microorganisms. Accordingly, we evaluated O-allyl-lawsone (OAL) antiparasitic and antifungal activity free and encapsulated in 2-hydroxypropyl-ß-cyclodextrin (OAL MKN) against Trypanosoma cruzi and Sporothrix spp. OAL and OAL MKN were synthesized and characterized by physicochemical methods. The IC50 values of OAL against T. cruzi were 2.4 µM and 96.8 µM, considering epimastigotes and trypomastigotes, respectively. At the same time, OAL MKN exhibited a lower IC50 value (0.5 µM) for both trypanosome forms and low toxicity for mammalian cells. Additionally, the encapsulation showed a selectivity index approximately 240 times higher than that of benznidazole. Regarding antifungal activity, OAL and OAL MKN inhibited Sporothrix brasiliensis growth at 16 µM, while Sporothrix schenckii was inhibited at 32 µM. OAL MKN also exhibited higher selectivity toward fungus than mammalian cells. In conclusion, we described the encapsulation of O-allyl-lawsone in 2-hydroxypropyl-ß-cyclodextrin, increasing the antiparasitic activity compared with the free form and reducing the cytotoxicity and increasing the selectivity towardSporothrix yeasts and the T. cruzi trypomastigote form. This study highlights the potential development of this inclusion complex as an antiparasitic and antifungal agent to treat neglected diseases.

Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo.

OBJECTIVE: The present study aimed to investigate five triazole compounds as P2X7R inhibitors and evaluate their ability to reduce acute inflammation in vivo. MATERIAL: The synthetic compounds were labeled 5e, 8h, 9i, 11, and 12. TREATMENT: We administered 500 ng/kg triazole analogs in vivo, (1-10 µM) in vitro, and 1000 mg/kg for toxicological assays. METHODS: For this, we used in vitro experiments, such as platelet aggregation, in vivo experiments of paw edema and peritonitis in mice, and in silico experiments. RESULTS: The tested substances 5e, 8h, 9i, 11, and 12 produced a significant reduction in paw edema. Molecules 5e, 8h, 9i, 11, and 12 inhibited carrageenan-induced peritonitis. Substances 5e, 8h, 9i, 11, and 12 showed an anticoagulant effect, and 5e at a concentration of 10 µM acted as a procoagulant. All derivatives, except for 11, had pharmacokinetic, physicochemical, and toxicological properties suitable for substances that are candidates for new drugs. In addition, the ADMET risk assessment shows that derivatives 8h, 11, 5e, and 9i have high pharmacological potential. Finally, docking tests indicated that the derivatives have binding energies comparable to the reference antagonist with a competitive inhibition profile. CONCLUSIONS: Together, the results indicate that the molecules tested as antagonist drugs of P2X7R had anti-inflammatory action against the acute inflammatory response.

Recent Synthetic Advances on the Use of Diazo Compounds Catalyzed by Metalloporphyrins.

Diazo compounds are organic substances that are often used as precursors in organic synthesis like cyclization reactions, olefinations, cyclopropanations, cyclopropenations, rearrangements, and carbene or metallocarbene insertions into C-H, N-H, O-H, S-H, and Si-H bonds. Typically, reactions from diazo compounds are catalyzed by transition metals with various ligands that modulate the capacity and selectivity of the catalyst. These ligands can modify and enhance chemoselectivity in the substrate, regioselectivity and enantioselectivity by reflecting these preferences in the products. Porphyrins have been used as catalysts in several important reactions for organic synthesis and also in several medicinal applications. In the chemistry of diazo compounds, porphyrins are very efficient as catalysts when complexed with low-cost metals (e.g., Fe and Co) and, therefore, in recent years, this has been the subject of significant research. This review will summarize the advances in the studies involving the field of diazo compounds catalyzed by metalloporphyrins (M-Porph, M = Fe, Ru, Os, Co, Rh, Ir) in the last five years to provide a clear overview and possible opportunities for future applications. Also, at the end of this review, the properties of artificial metalloenzymes and hemoproteins as biocatalysts for a broad range of applications, namely those concerning carbene-transfer reactions, will be considered.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Naphthoquinone Sulfonamides and Sulfonate Ester Derivatives as P2X7 Inhibitors.

ATP acts in the extracellular environment as an important signal, activating a family of receptors called purinergic receptors. In recent years, interest in the potential therapeutics of purinergic components, including agonists and antagonists of receptors, has increased. Currently, many observations have indicated that ATP acts as an important mediator of inflammatory responses and, when found in high concentrations in the extracellular space, is related to the activation of the P2X7 purinergic receptor. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Sulfonamide derivatives have been reported to be potent inhibitors of P2X receptors. In this study, ten naphthoquinone sulfonamide derivatives and five naphthoquinone sulfonate ester derivatives were tested for their inhibitory activity on the P2X7 receptor expressed in peritoneal macrophages. Some compounds showed promising results, displaying IC50 values lower than that of A740003. Molecular docking and dynamic studies also indicated that the active compounds bind to an allosteric site on P2X7R. The binding free energy indicates that sulfonamides have an affinity for the P2X7 receptor similar to A740003. Therefore, the compounds studied herein present potential P2X7R inhibition.

The evaluation of in vitro antichagasic and anti-SARS-CoV-2 potential of inclusion complexes of ß- and methyl-ß-cyclodextrin with naphthoquinone.

The compound 3a,10b-dihydro-1H-cyclopenta[b]naphtho[2,3-d]furan-5,10-dione (IVS320) is a naphthoquinone with antifungal and antichagasic potential, which however has low aqueous solubility. To increase bioavailability, inclusion complexes with ß-cyclodextrin (ßCD) and methyl-ß-cyclodextrin (MßCD) were prepared by physical mixture (PM), kneading (KN) and rotary evaporation (RE), and their in vitro anti-SARS-CoV-2 and antichagasic potential was assessed. The formation of inclusion complexes led to a change in the physicochemical characteristics compared to IVS320 alone as well as a decrease in crystallinity degree that reached 74.44% for the IVS320-MßCD one prepared by RE. The IVS320 and IVS320-MßCD/RE system exhibited anti-SARS-CoV-2 activity, showing half maximal effective concentrations (EC50) of 0.47 and 1.22 µg/mL, respectively. Molecular docking simulation suggested IVS320 ability to interact with the SARS-CoV-2 viral protein. Finally, the highest antichagasic activity, expressed as percentage of Tripanosoma cruzi growth inhibition, was observed with IVS320-ßCD/KN (70%) and IVS320-MßCD/PM (72%), while IVS320 alone exhibited only approximately 48% inhibition at the highest concentration (100 µg/mL).

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice.

AIMS/HYPOTHESIS: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. METHODS: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5-6.0 mg kg-1 day-1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. RESULTS: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. CONCLUSIONS/INTERPRETATION: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.

Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors.

The P2X7 receptor (P2X7R) is an ion channel that promotes the passage of ions through the membrane through brief stimulation once activated by ATP, its endogenous opener. However, prolonged stimulation with ATP, which occurs in pathological processes, opens a nonselective pore in the plasma membrane, allowing the passage of large molecules and leading to cytokine release or even cell death. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Considering the booming of biomass upgrading reactions in recent years and the continued efforts to synthesize biologically active molecules containing the 1,2,3-triazole ring, in the present work, we aimed to investigate whether triazole-linked menadione-furan derivatives could present P2X7R inhibitory activity. The novel compounds were tested for their inhibitory activity on ATP-induced dye uptake in peritoneal macrophages. Some have shown promising results, having displayed IC50 values lower than that of the P2X7R inhibitor BBG. Molecular docking studies also indicated that the active compounds bind to an allosteric site on P2X7R, presenting potential P2X7R inhibition.

Antitumoral effect of novel synthetic 8-hydroxy-2-((4-nitrophenyl)thio)naphthalene-1,4-dione (CNN16) via ROS-mediated DNA damage, apoptosis and anti-migratory effect in colon cancer cell line.

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 µM in HCT-116, and 9.36, 10.77, and 24.57 µM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

Multicomponent Reactions (MCRs) with o-Quinone Methides.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho-quinone methide intermediates (o-QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron-rich dienophiles in inverse-electron demand hetero-Diels-Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

Betanin as a multipath oxidative stress and inflammation modulator: a beetroot pigment with protective effects on cardiovascular disease pathogenesis.

Oxidative stress is a common physiopathological condition enrolled in risk factors for cardiovascular diseases. Individuals in such a redox imbalance status present endothelial dysfunctions and inflammation, reaching the onset of heart disease. Phytochemicals are able to attenuate the main mechanisms of oxidative stress and inflammation and should be considered as supportive therapies to manage risk factors for cardiovascular diseases. Beetroot (Beta vulgaris L.) is a rich source of bioactive compounds, including betanin (betanidin-5-O-ß-glucoside), a pigment displaying the potential to alleviate oxidative stress and inflammantion, as previously demonstrated in preclinical trials. Betanin resists gastrointestinal digestion, is absorbed by the epithelial cells of intestinal mucosa and reaches the plasma in its active form. Betanin displays free-radical scavenger ability through hydrogen or electron donation, preserving lipid structures and LDL particles while inducing the transcription of antioxidant genes through the nuclear factor erythroid-2-related factor 2 and, simultaneously, suppressing the pro-inflammatory nuclear factor kappa-B pathways. This review discusses the anti-radical and gene regulatory cardioprotective activities of betanin in the pathophysiology of endothelial damage and atherogenesis, the main conditions for cardiovascular disease. In addition, betanin influences on these multipath cellular signals and aiding in reducing cardiovascular disorders is proposed.

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line.

The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Chemoselective Synthesis of Mannich Adducts from 1,4-Naphthoquinones and Profile as Autophagic Inducers in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, accounting for approximately 90% of all oral cancers, and is the eighth most common cancer in men. Cisplatin and carboplatin are the main chemotherapy drugs used in the clinic. However, in addition to their serious side effects, such as damage to the nervous system and kidneys, there is also drug resistance. Thus, the development of new drugs becomes of great importance. Naphthoquinones have been described with antitumor activity. Some of them are found in nature, but semi synthesis has been used as strategy to find new chemical entities for the treatment of cancer. In the present study, we promote a multiple component reaction (MCR) among lawsone, arylaldehydes, and benzylamine to produce sixteen chemoselectively derivated Mannich adducts of 1,4-naphthoquinones in good yield (up to 97%). The antitumor activities and molecular mechanisms of action of these compounds were investigated in OSCC models and the compound 6a induced cytotoxicity in three different tumor cell lines (OSCC4, OSCC9, and OSCC25) and was more selective (IS > 2) for tumor cells than the chemotropic drug carboplatin and the controls lapachol and shikonin, which are chemically similar compounds with cytotoxic effects. The 6a selectively and significantly reduced the amount of cell colony growth, was not hemolytic, and tolerable in mice with no serious side effects at a concentration of 100 mg/kg with a LD50 of 150 mg/kg. The new compound is biologically stable with a profile similar to carboplatin. Morphologically, 6a does not induce cell retraction or membrane blebs, but it does induce intense vesicle formation and late emergence of membrane bubbles. Exploring the mechanism of cell death induction, compound 6a does not induce ROS formation, and cell viability was not affected by inhibitors of apoptosis (ZVAD) and necroptosis (necrostatin 1). Autophagy followed by a late apoptosis process appears to be the death-inducing pathway of 6a, as observed by increased viability by the autophagy inhibitor (3-MA) and by the appearance of autophagosomes, later triggering a process of late apoptosis with the presence of caspase 3/7 and DNA fragmentation. Molecular modeling suggests the ability of the compound to bind to topoisomerase I and II and with greater affinity to hPKM2 enzyme than controls, which could explain the mechanism of cell death by autophagy. Finally, the in-silico prediction of drug-relevant properties showed that compound 6a has a good pharmacokinetic profile when compared to carboplatin and doxorubicin. Among the sixteen naphthoquinones tested, compound 6a was the most effective and is highly selective and well tolerated in animals. The induction of cell death in OSCC through autophagy followed by late apoptosis possibly via inhibition of the PKM2 enzyme points to a promising potential of 6a as a new preclinical anticancer candidate.

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis.

Several low molecular weight naphthoquinones are very useful in organic synthesis. These compounds have given rise to thousands of other naphthoquinones that have been tested against various microorganisms and pharmacological targets, including being used in the preparation of several drugs that are on the pharmaceutical market. Among these naphthoquinones, the series of compounds prepared from 1,2-naphthoquinone-4-sulfonic acid salts (ß-NQS) stands out. In addition to being used in organic synthesis, they are excellent analytical derivatization reagents to spectrophotometrically determine drugs containing primary and secondary amino groups. This review summarizes the literature involving ß-NQS.

Menadione: a platform and a target to valuable compounds synthesis.

Naphthoquinones are important natural or synthetic compounds belonging to the general class of quinones. Many compounds in this class have become drugs that are on the pharmaceutical market for the treatment of various diseases. A special naphthoquinone derivative is menadione, a synthetic naphthoquinone belonging to the vitamin K group. This compound can be synthesized by different methods and it has a broad range of biological and synthetic applications, which will be highlighted in this review.

In Vitro and In Vivo Antifungal Activity of Buparvaquone against Sporothrix brasiliensis.

Sporotrichosis has become an important zoonosis in Brazil, and Sporothrix brasiliensis is the primary species transmitted by cats. Improvement of animal treatment will help control and limit the spread and geographic expansion of sporotrichosis. Accordingly, buparvaquone, an antiprotozoal hydroxynaphthoquinone agent marketed as Butalex, was evaluated in vitro and in vivo against feline-borne isolates of S. brasiliensis. Buparvaquone inhibited in vitro fungal growth at concentrations 4-fold lower than itraconazole (the first-choice antifungal used for sporotrichosis) and was 408 times more selective for S. brasiliensis than mammalian cells. Yeasts treated with a subinhibitory concentration of buparvaquone exhibited mitochondrial dysfunction, reactive oxygen species and neutral lipid accumulation, and impaired plasma membranes. Scanning electron microscopy images also revealed buparvaquone altered cell wall integrity and induced cell disruption. In vivo experiments in a Galleria mellonella model revealed that buparvaquone (single dose of 5 mg/kg of body weight) is more effective than itraconazole against infections with S. brasiliensis yeasts. Combined, our results indicate that buparvaquone has a great in vitro and in vivo antifungal activity against S. brasiliensis, revealing the potential application of this drug as an alternative treatment for feline sporotrichosis.