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The treatment of central nervous system (CNS) malignancies, including brain cancers, is limited by a number of obstructions, including the blood-brain barrier (BBB), the heterogeneity and high invasiveness of tumors, the inaccessibility of tissues for early diagnosis and effective surgery, and anti-cancer drug resistance. Therapies employing nanomedicine have been shown to facilitate drug penetration across the BBB and maintain biodistribution and accumulation of therapeutic agents at the desired target site. The application of lipid-, polymer-, or metal-based nanocarriers represents an advanced drug delivery system for a growing group of anti-cancer chemicals. The nanocarrier surface is designed to contain an active ligand (cancer cell marker or antibody)-binding structure which can be modified to target specific cancer cells. Glioblastoma, ependymoma, neuroblastoma, medulloblastoma, and primary CNS lymphomas were recently targeted by easily absorbed nanocarriers. The metal- (such as transferrin drug-loaded systems), polymer- (nanocapsules and nanospheres), or lipid- (such as sulfatide-containing nanoliposomes)-based nano-vehicles were loaded with apoptosis- and/or ferroptosis-stimulating agents and demonstrated promising anti-cancer effects. This review aims to discuss effective nanomedicine approaches designed to overcome the current limitations in the therapy of brain cancers and age-dependent neurodegenerative disorders. To accent current obstacles for successful CNS-based cancer therapy, we discuss nanomedicine perspectives and limitations of nanodrug use associated with the specificity of nervous tissue characteristics and the effects nanocarriers have on cognition.

Alzheimers disease (AD) is one of the most common neurodegenerative diseases in existence. It is characterized by an impaired cognitive function that is due to a progressive loss of neurons in the brain. Extracellular -amyloid (A) plaques are the main pathological features of the disease. In addition to abnormal protein aggregation, increased mitochondrial fragmentation, altered expression of the genes involved in mitochondrial biogenesis, disruptions in the ERmitochondria interaction, and mitophagy are observed. Reactive oxygen species are known to affect A expression and aggregation. In turn, oligomeric and aggregated A cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of A on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimers disease.

Epigenetic changes associated with histone modifications play an important role in the emergence and maintenance of the phenotype of various cancer types. In contrast to direct mutations in the main DNA sequence, these changes are reversible, which makes the development of inhibitors of enzymes of post-translational histone modifications one of the most promising strategies for the creation of anticancer drugs. To date, a wide variety of histone modifications have been found that play an important role in the regulation of chromatin state, gene expression, and other nuclear events. This review examines the main features of the most common and studied epigenetic histone modifications with a proven role in the pathogenesis of a wide range of malignant neoplasms: acetylation / deacetylation and methylation / demethylation of histone proteins, as well as the role of enzymes of the HAT / HDAC and HMT / HDMT families in the development of oncological pathologies. The data on the relationship between histone modifications and certain types of cancer are presented and discussed. Special attention is devoted to the consideration of various strategies for the development of epigenetic inhibitors. The main directions of the development of inhibitors of histone modifications are analyzed and effective strategies for their creation are identified and discussed. The most promising strategy is the use of multitarget drugs, which will affect multiple molecular targets of cancer. A critical analysis of the current status of approved epigenetic anticancer drugs has also been performed.

The reaction of DL-valine hydroxamic acid with triacetonamine proceeds as the N,N'-regioselective condensation to form (±)-1-hydroxy-3-isopropyl-7,7,9,9-tetramethyl-1,4,8-triazaspiro[4,5]decan-2-one. A study of the antimetastatic and antitumor activities of the resulting hydroxamic acid in vivo by the combined therapy with a cytostatic of the alkylation type on a model of experimental transplanted mouse melanoma B16 showed that the compound is capable of increasing the sensitivity of the tumor to the known antitumor drug cyclophosphamide applied at a subtherapeutic dose. The chemosensitizing activity of hydroxamic acid combined with cyclophosphamide led to an almost twofold increase in the antitumor effect of the cytostatic and a marked decrease in the number of metastases, which showed up as an increase in the metastasis inhibition index (MII) to 74%.

The use of nanoparticles dramatically increases the safety and efficacy of the most common anticancer drugs. The main advantages of nano-drugs and delivery systems based on nano-technology are effective targeting, delayed release, increased half-life, and less systemic toxicity. The use of nano-carriers has led to significant improvements in drug delivery to targets compared with traditional administration of these drugs. In this review, the main tendencies in nano-drug formulations as well as factors limiting their use in clinical settings are discussed. Additionally, the current status of approved nano-drugs for cancer treatment is reviewed.

To date, a lot of nanotechnological optitions are available for targeted drug delivery. Extracellular vesicles (EVs) are membrane structures that cells use for storage, transport, communication, and signaling. Recent research has focused on EVs as natural nanoparticles for drug delivery. This review sheds light on the application of EVs in cancer therapy, such as targeted chemotherapy, gene therapy, and vaccine development. Aspects of biogenesis, isolation, targeting, and loading of EVs are discussed in detail.

Using the methodology of "click" chemistry, a series of conjugates of 3,5-bis(benzylidene)-1-(prop-2-yn)piperidin-4-ones with 4-alkyl-3-azidomethyl-2-ethoxy-2,5-dihydro-5H-1,2 oxaphosphol 2-oxides was synthesized. All newly obtained compounds 8-18 were characterized by

Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.

Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, -synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.

Cyclic hydroxamic acids (CHAs) based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. Among the synthesized CHAs two compounds-hits exhibiting the multipharmacological type of the antineoplastic activity have been identified. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species (ROS) and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases (HDACs), involved in the epigenetic regulation of tumor genesis. Thus, the synthesized CHAs may be considered as a promising basis for creating potential oncolytics.

Background:In this review we survey medical treatments and research strategies, and we discuss why they have failed to cure degenerative disc diseases or even slow down the degenerative process.Objective:We seek to stimulate discussion with respect to changing the medical paradigm associated with treatments and research applied to degenerative disc diseases.Method Proposal:We summarize a Biological Transformation therapy for curing chronic inflammations and degenerative disc diseases, as was previously described in the book Biological Transformations controlled by the Mind Volume 1.Preliminary Studies:A single-patient case study is presented that documents complete recovery from an advanced lumbar bilateral discopathy and long-term hypertrophic chronic rhinitis by application of the method proposed.Conclusion:Biological transformations controlled by the mind can be applied by men and women in order to improve their quality of life and cure degenerative disc diseases and chronic inflammations illnesses.

This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and endometriosis-associated ovarian tumors are important problems that require further study in the context of advanced therapeutic strategies to provide maximal health benefits to patients.

Previously unknown conjugates of the natural sesquiterpene lactone arteannuin B, which was isolated from Artemisia annua, were synthesized via Michael reactions with pharmacophoric amines and tested in vitro for cytotoxic activity. The compounds were shown to exhibit antiproliferative properties for various tumor cell lines. The most active derivatives had IC50 values of 8–36 μM, which exceeded that of starting arteannuin B. Practically all obtained conjugates were found to modulate glycolysis in MCF7 tumor cells. The lead compound was the conjugate with 3-ethoxycarbonylpiperidine, which could be considered a platform for developing antitumor drugs.

Epigenetic regulation by microRNAs (miRs) demonstrated a promising therapeutic potential of these molecules to regulate genetic activity in different cancers, including colorectal cancers (CRCs). The RNA-based therapy does not change genetic codes in tumor cells but can silence oncogenes and/or reactivate inhibited tumor suppressor genes. In many cancers, specific miRs were shown to promote or stop tumor progression. Among confirmed and powerful epigenetic regulators of colon carcinogenesis and development of resistance are onco-miRs, which include let-7, miR-21, miR-22, miR-23a, miR-27a, miR-34, miR-92, miR-96, miR-125b, miR-135b, miR-182, miR-200c, miR-203, miR-221, miR-421, miR-451, and others. Moreover, various tumor-suppressor miRs (miR-15b-5b, miR-18a, miR-20b, miR-22, miR-96, miR-139-5p, miR-145, miR-149, miR-197, miR-199b, miR-203, miR-214, miR-218, miR-320, miR-375-3p, miR-409-3p, miR-450b-5p, miR-494, miR-577, miR-874, and others) were found silenced in drug-resistant CRCs. Re-expression of tumor suppressor miR is complicated by the chemical nature of miRs that are not long-lasting compounds and require protection from the enzymatic degradation. Several recent studies explored application of miRs using nanocarrier complexes. This study critically describes the most successfully tested nanoparticle complexes used for intracellular delivery of nuclear acids and miRs, including micelles, liposomes, inorganic and polymeric NPs, dendrimers, and aptamers. Nanocarriers shield incorporated miRs and improve the agent stability in circulation. Attachment of antibodies and/or specific peptide or ligands facilitates cell-targeted miR delivery. Addressing in vivo challenges, a broad spectrum of non-toxic materials has been tested and indicated reliable advantages of lipid-based (lipoplexes) and polymer-based liposomes. Recent cutting-edge developments indicated that lipid-based complexes with multiple cargo, including several miRs, are the most effective approach to eradicate drug-resistant tumors. Focusing on CRC-specific miRs, this review provides a guidance and insights towards the most promising direction to achieve dramatic reduction in tumor growth and metastasis using miR-nanocarrier complexes.

Simple Summary There is no doubt that the need for new effective methods of cancer treatment remains challenging, as cancer is the second cause of death based on the number of cases in the world. In this review, we investigated the role of one of the leading determinants in the development and progression of various types of cancer—oxidative stress and inflammation, as well as clinical and experimental data from the studies of promising drugs of natural origin, such as flavonoids, that target these stages of oncogenesis. This can all help in the expansion and systematization of the existing knowledge regarding the fight against cancer, the facilitation of the development of effective anti-cancer drugs, and the progression of research in this field, in order to improve the treatment of these disorders. Abstract Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood–brain barrier. According to the in vitro testing, hydroxamic acids 15 and 25, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against β-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer’s disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid 15 restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer’s disease.

In the case of various pathologies, an imbalance between ROS generation and the endogenous AOS can be observed, which leads to excessive ROS accumulation, intensification of LPO processes, and oxidative stress. For the prevention of diseases associated with oxidative stress, drugs with antioxidant activity can be used. The cytotoxic, antioxidant, and NO-donor properties of the new hybrid compound B6NO (di(3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridinium) salt of 2-(nitrooxy)butanedioic acid) were studied. It was determined that B6NO chelates iron ions by 94%, which indicates B6NO’s ability to block the Fenton reaction. The hybrid compound B6NO inhibits the process of initiated lipid peroxidation more effectively than pyridoxine. It was shown that B6NO exhibits antioxidant properties by decreasing ROS concentration in normal cells during the oxidative stress induction by tert-Butyl peroxide. At the same time, the B6NO antioxidant activity on tumor cells was significantly lower. B6NO significantly increases the intracellular nitrogen monoxide accumulation and showed low cytotoxicity for normal cells (IC50 &gt, 4 mM). Thus, the results indicate a high potential of the B6NO as an antioxidant compound.

Ras proteins have been reported to play key role in oncologic diseases. Ras proteins are associated with cellular membranes for its carcinogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase is responsible for a type of Ras membrane targeting, which leads to cancer origin and progression. Inhibitors of farnesyltransferase have been developed as novel anticancer agents. In this review, the role of farnesyltransferase in cancer progression and development has been discussed. Further, the current status of development of farnesyltransferase inhibitors for cancer prevention and treatment has also been reviewed.

Previously unknown conjugates of substituted piperazines with various functional groups on the N atom and the natural sesquiterpene lactones alantolactone, isoalantolactone, and alloalantolactone, the main constituents of the plant Inula helenium, were synthesized using Michael reaction. Cytotoxicity of the natural sesquiterpene lactones and their conjugates was studied in vitro. The compounds were shown to exhibit antiproliferative properties against various tumor cell lines.

Alkaloids, secondary plant metabolites, are used in traditional medicine in many countries to treat various pathological conditions. Securinine, a unique indolizidine alkaloid combining four cycles, “6-azobicyclo[3.2.1]octane” as a key structure fused with α,β-unsaturated-γ-lactone and piperidine ring, has a broad spectrum of actions including anti-inflammatory, antibacterial, neuroprotective and antitumor, and has been previously used in medical practice. It has several reactive centers, which are double bonds at positions 12–13 and 14–15, and this is a challenging scaffold for the synthesis of biologically active compounds. In this review, works on the production of modified securinine derivatives and their biological activity are addressed. Both monovalent and bivalent derivatives that are most promising in our opinion, and have potential for further research, are considered.

Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.Sintezirovan riad tsiklicheskikh gidroksamovykh kislot na osnove khinazolin-4(3N)-ona i digidrokhinazolin-4(1N)-ona. Issledovany antioksidantnye i zhelezokhelatiruiushchie svoĭstva dannykh soedineniĭ, ikh vliianie na aktivnost' fermenta gistondeatsetilazy i tsitotoksicheskoe deĭstvie po otnosheniiu k kletkam razlichnykh opukholevykh liniĭ. Vyiavleno dva soedineniia-khita, kotorye proiavliaiut mul'tifarmakologicheskiĭ tip antineoplasticheskoĭ aktivnosti. Dlia étikh veshchestv pokazano tsitotoksicheskoe deĭstvie po otnosheniiu k kletkam kartsinomy legkogo cheloveka A549 i adenokartsinomy molochnoĭ zhelezy MCF-7, kotoroe obuslovleno sposobnost'iu modulirovat' uroven' aktivnykh form kisloroda i khelatirovat' iony dvukhvalentnogo zheleza, a takzhe proiavliat' ingibiruiushchee deĭstvie v otnoshenii metallofermentov gistondeatsetilaz, uchastvuiushchikh v épigeneticheskoĭ reguliatsii opukholevogo geneza. Éto pozvoliaet rassmatrivat' gidroksamovye kisloty v kachestve osnovy dlia sozdaniia potentsial'nykh onkolitikov.

Hydroxamic acids are a promising class of chemical compounds with proven antitumor potential, primarily due to their ability to inhibit the activity of histone deacetylase enzymes. The analysis of modern experimental data shows a wide range of biological activities of hydroxamic acids, which make them equally worthy candidates for the fight against neuropathologies. A characteristic feature of hydroxamic acids is their ability to act simultaneously on several promising molecular targets for the correction of both neuropathologies and oncological diseases, thereby exhibiting multifunctionality. This review discusses the effect of hydroxamic acids on key parts of cancer and neurodegenerative disorders' pathogenesis. Pathological changes in the processes associated with oxidative stress, the functioning of mitochondria, and the activity of metal enzymes of the class of histone deacetylases, as the main links in the epigenetic regulation of pathological conditions, are such molecular targets.

Aims: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. Background: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. Objective: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. Methods: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. Result: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. Conclusion: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Background: The conjugates of the sesquiterpene lactone of the eremophilane series of 6- hydroxyxanthanodiene with hydrogenated azines (piperidines and piperazines) have been synthesized and identified by NMR spectrometer. Objective: A lactone with an unusual skeleton “6-hydroxyxanthanodiene” was extracted from the plant Elecampane (Inula helenium L) and identified various species with NMR spectrometer. Methods: The cytotoxic, mitochondrial, and antioxidant activities on different tumor lines such as A549, HCT116, RD and Jurkat were investigated and determined possible mechanisms. Results: The results showed that the most potent compound was IIIi exhibiting highest cytotoxicity against RD cells (IC50 25.23 ± 0.04 μM), depolarized the mitochondrial membrane and was an effective antioxidant (IC50 inhibition of LP 10.68 ± 3.21 μM) without any toxic side effect on healthy cells. Conclusion: The conjugates of sesquiterpene lactone 6-hydroxyxanthanodiene III and hydrogenated azines may help to design potential promising anticancer drugs.

New diphenylsulfimide derivatives containing substituents with the 2,6-di-tert-butylphenol moiety at the nitrogen atom were synthesized. Their molecular structures were established by X-ray diffraction. Antioxidant activity was experimentally evaluated by spectrophotometry based on hydrogen transfer to the stable radicals, namely, 2,2-diphenyl-1-picrylhydrazyl and the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS·+), and using in vitro lipid peroxidation in rat brain and liver homogenates. The presence of phenol and diphenylsulfimide moieties in one molecule leads to a significant enhancement of antioxidant activity. The new compounds exhibit moderate inhibitory activity against enzymes involved in carbohydrate and lipid metabolism. The evaluation of antiglycation activity showed that the new sulfimides taken at a concentration of 100 μmol L–1 have activity comparable with that of aminoguanidine.

The paper considers the influence of the structure of aminoadamantane–carbazole conjugates linked by five different spacers on their ability to inhibit acetylcholinesterase, butyrylcholinesterase (BChE), and carboxylesterase, the radical scavenging and mitoprotective activity, and tubulin polymerization. The nature of the spacer was found to be determinant for the appearance of anti-BChE and radical-scavenging activity. Aminoadamantane–carbazole conjugates linked by flexible spacers proved to be most effective in these assays. The influence of the conjugates on mitochondrial functions and tubulin polymerization largely depends on the structure of the carbazole moiety. A series of lead compounds promising for further study was identified as potential drugs for the treatment of neurodegenerative diseases, in particular, Alzheimer’s disease.

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

Alzheimer’s disease has a complex multifactorial nature; therefore, a promising approach for the development of efficient therapeutic agents is the concept of multitarget drugs, which affect several biological targets involved in the pathogenesis of the disease. We developed a synthetic algorithm for conjugating several pharmacophoric ligands acting on the key stages of pathogenesis of several neurodegenerative diseases and synthesized hybrid structures combining the γ-carboline fragment of Dimebon with carbazole and tetrahydrocarbazole moieties. Using the complex primary screening system the structures have been revealed that combine the high inhibitory activity and selectivity towards butyrylcholinesterase with the radical-scavenging activity and the ability to potentiate tubulin polymerization to microtubules with a normal structure and/or prevent mitochondrial permeability transition. The lead compound was identified for future optimization and development of new multi-target drugs against neurodegenerative diseases combining the cognitive-stimulating and neuroprotective potentials.

Novel gold(I) complexes, PPh3AuSR (1) and [(Ph3PAu)2SR]2(BF4)2 (2), with a protective antioxidant group R (R = 3,5-di-tert-butyl-4-hydroxyphenyl) were synthesized and characterized by 1H, 13C, 31P NMR, IR and elemental analyses. The crystal structures of compounds 1 and 2 were determined by X-ray diffraction. Compound 2 has a cluster structure with four Au–Au bonds in the crystal. The tetragold(I) dication is composed of four PPh3Au units with bridging sulfur atoms, where the Au4 moiety has a distorted tetrahedral geometry. The biological impact of gold complexes 1 and 2, and their precursors (RSH and AuPPh3Cl), on lipid peroxidation, mitochondrial functions, the tubulin polymerization, activity of glutathione reductase and cell viability were investigated. A comparative study of the structure–activity relationship was performed. We found that RSH and Au complexes 1 and 2 as opposed to AuPPh3Cl, prevented Fe3+ and tBHP-induced lipid peroxidation in isolated mitochondria. The number of 2,6-di-tert-butylphenol fragments influences the inhibitory effect. AuPPh3Cl induced swelling and depolarization of mitochondria, whereas RSH and the gold complexes 1 and 2, containing 2,6-di-tert-butylphenol groups, showed little to null effect. The thiol ligand RSH and AuPPh3Cl as well as gold complexes 1 and 2 have no impact on tubulin polymerization. The gold complexes were found to inhibit glutathione reductase. The compounds were tested for cytotoxicity against a primary culture of rat cerebellar granule cells. A high toxicity was determined for AuPPh3Cl, while introduction of antioxidant phenol groups decreased the cytotoxicity of the Au complexes. These results open up scope for the design of novel low toxic, gold based pharmacological agents.

Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.

Objective:Glioblastoma is a highly aggressive and invasive brain and Central Nervous System (CNS) tumor. Current treatment options do not prolong overall survival significantly because the disease is highly prone to relapse. Therefore, research to find new therapies is of paramount importance. It has been discovered that glioblastomas contain a population of cells with stem-like properties and that these cells are may be responsible for tumor recurrence.Methods:A review of relevant papers and clinical trials in the field was conducted. A PubMed search with related keywords was used to gather the data. For example, “glioblastoma stem cells AND WNT signaling” is an example used to find information on clinical trials using the database ClinicalTrials.gov.Results:Cancer stem cell research has several fundamental issues and uncertainties that should be taken into consideration. Theoretically, a number of treatment options that target glioblastoma stem cells are available for patients. However, only a few of them have obtained promising results in clinical trials. Several strategies are still under investigation.Conclusion:The majority of treatments to target cancer stem cells have failed during clinical trials. Taking into account a number of biases in the field and the number of unsuccessful investigations, the application of the cancer stem cells concept is questionable in clinical settings, at least with respect to glioblastoma.

Background:Sleep disorders have emerged as potential cancer risk factors.Objective:This review discusses the relationships between sleep, obesity, and breathing disorders with concomitant risks of developing cancer.Results:Sleep disorders result in abnormal expression of clock genes, decreased immunity, and melatonin release disruption. Therefore, these disorders may contribute to cancer development. Moreover, in sleep breathing disorder, which is frequently experienced by obese persons, the sufferer experiences intermittent hypoxia that may stimulate cancer cell proliferation.Discussion:During short- or long- duration sleep, sleep-wake rhythm disruption may occur. Insomnia and obstructive sleep apnea increase cancer risks. In short sleepers, an increased risk of stomach cancer, esophageal squamous cell cancer, and breast cancer was observed. Among long sleepers (>9 hours), the risk of some hematologic malignancies is elevated.Conclusion:Several factors including insomnia, circadian disruption, obesity, and intermittent hypoxia in obstructive sleep apnea are contributing risk factors for increased risk of several types of cancers. However, further studies are needed to determine the more significant of these risk factors and their interactions.

A series of stereospecific conjugates of the naturally occurring scaffold - alkaloid securinine 1 - was synthesized using the Lewis acid catalyst ytterbium triflate. The study of their antioxidant and cytoprotective properties showed that these compounds can be considered as potential neuroprotectors. Among these compounds, a leader substance is identified - securinine conjugate with tryptamine. Further research has confirmed that this compound is capable to protecting neuronal cells from the toxic effects of glutamate and iron ions. Based on these results, derivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.A series of stereospecific conjugates of the naturally occurring scaffold - alkaloid securinine 1 - was synthesized using the Lewis acid catalyst ytterbium triflate. The study of their antioxidant and cytoprotective properties showed that these compounds can be considered as potential neuroprotectors. Among these compounds, a leader substance is identified - securinine conjugate with tryptamine. Further research has confirmed that this compound is capable to protecting neuronal cells from the toxic effects of glutamate and iron ions. Based on these results, derivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

The reaction of DL-valine hydroxamic acid with triacetonamine passes as N, N′-regioselective cyclocondensation to form (±) -1-hydroxy-3-isopropyl-7,7,9,9-tetramethyl-1,4,8-triazaspiro [4.5] decan-2-one. In vivo study of chemosensitizing antitumor activity of spirocyclic hydroxamic acid by the combination therapy with cytostatics of alkylating type cisplatin and cyclophosphamide in the model of leukemia P388 was investigated. It was shown the ability of this acid to increase the sensitivity of the tumor to the action of cisplatin and cyclophosphamide applied at doses below therapeutic. Chemosensitizing activity of spirocyclic hydroxamic acid has made it possible to achieve an appreciable level of survival of tumor-bearing animals (up to 37.5%).

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.

Novel 3,5-bis(arylidene)-4-piperidones modified with diethyl[(aryl)methyl]phosphonate moiety attached to the piperidone nitrogen atom have been synthesized by crotonic condensation of aromatic aldehydes with diethyl[(4-oxopiperidin-1-yl)(aryl)methyl]phosphonates in the presence of LiClO4/Et3N system or acetonitrile solution of boron trifluoride etherate. The synthesized phosphonate derivatives of 3,5-bis(arylidene)-4-piperidone series displayed inhibitory properties toward RD, PC3, HCT116, and MCF7 human cancer cell lines with IC50 values in the range of 2.5–8.5 μM, as assessed by an in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Oxidative stress and mitochondrial disturbances are the common and important causative factors of aging, and play an important role in the late onset of sporadic neurodegenerative diseases, including Alzheimer disease (AD). Furthermore, emerging evidence from in vitro and in vivo disease models suggests that oxidative stress and increased vulnerability to induction of mitochondrial permeability transition leads to the pathogenesis of the neurological disorders. Towards the goals of developing effective neuroprotectors, this article describes the synthesis and neuroprotective studies of various derivatives of the naturally occurring alkaloid securinine, based on which a lead compound, allomargaritarine (a diastereomer of margaritarine), was identified as an effective therapeutic for neuroprotection. Allomargaritarine exhibits high antioxidant activity, and has significant mitoprotective effect on cellular models of neurodegeneration.

Compounds that act on mitochondrial functions are considered as promising drugs for the treatment of neurodegenerative diseases and age-related dementias. As a basis for the creation of such potential drugs, bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives were selected. Derivatives of cinnamic acid have a wide range of biological activities, which can be important for drugs aimed at the treatment of neurodegenerative diseases, in particular Alzheimer′s disease. In this work, the neuroprotective activity of bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives was studied. Among the compounds studied, lead substances 3, 4, and 7 have been identified. These compounds show no intrinsic toxicity and have a neuroprotective effect on the cellular model of neurodegeneration associated with calcium stress. The mechanism of their cytoprotective activity is probably due to the influence on mitochondrial functions, because these compounds effectively suppress the calcium-induced process of mitochondrial permeability jump. In addition, one of the substances investigated (7) has antioxidant properties, showing the ability to inhibit lipid peroxidation (LPO) of rat brain homogenate, which may be an additional mechanism of neuroprotective effect. The data obtained make it possible to recommend the investigated substances as a basis for the creation of effective neuroprotective drugs capable of influencing early stages of the development of neurodegenerative diseases., Соединения, направленно действующие на митохондриальные функции, рассматриваются как перспективные лекарственные препараты для лечения нейродегенеративных заболеваний и возрастных деменций. В качестве основы для создания таких потенциальных лекарственных средств были выбраны биоизостерные аналоги коричной кислоты и производные полиметоксибензолов. Производные коричной кислоты имеют широкий спектр биологических активностей, который может иметь значение для лекарственных препаратов, направленных на лечение нейродегенеративных заболеваний, в частности болезни Альцгеймера. В данной работе исследована нейропротекторная активность биоизостерных аналогов коричной кислоты и производных полиметоксибензолов. Среди исследованных соединений выявлены вещества-лидеры 3, 4 и 7. Эти соединения не проявляют собственной токсичности и оказывают нейропротекторный эффект на клеточной модели нейродегенерации, связанной с кальциевым стрессом. Механизм их цитопротекторной активности, возможно, обусловлен влиянием на функции митохондрий, поскольку эти соединения эффективно подавляют кальций-индуцированный процесс скачка митохондриальной проницаемости. Кроме того, одно из исследованных веществ (7) обладает антиоксидантными свойствами, проявляя способность к ингибированию перекисного окисления липидов (ПОЛ) гомогената мозга крыс, что может быть дополнительным механизмом нейропротекторного эффекта. Полученные данные позволяют рекомендовать исследованные вещества в качестве основы для создания эффективных нейропротекторных препаратов, способных повлиять на ранние стадии развития нейродегенеративных заболеваний.

Neuronal excitotoxicity which is induced by exposure to excessive extracellular glutamate is shown to be involved in neuronal cell death in acute brain injury and a number of neurological diseases. High concentration of glutamate induces calcium deregulation which results in mitochondrial calcium overload and mitochondrial depolarization that triggers the mechanism of cell death. Inhibition of mitochondrial calcium uptake could be potentially neuroprotective but complete inhibition of mitochondrial calcium uniporter could result in the loss of some physiological processes linked to Ca2+ in mitochondria. Here, we found that a novel compound, TG-2112x, can inhibit only the lower concentrations mitochondrial calcium uptake (induced by 100 nM-5 μM) but not the uptake induced by higher concentrations of calcium (10 μM and higher). This effect was not associated with changes in mitochondrial membrane potential and cellular respiration. However, a pre-treatment of neurons with TG-2112x protected the neurons against calcium overload upon application of toxic concentrations of glutamate. Thus, sequestration of mitochondrial calcium uptake protected the neurons against glutamate-induced mitochondrial depolarization and cell death. In our hands, TG-2112x was also protective against ionomycin-induced cell death. Hence, low rate mitochondrial calcium uptake plays an underestimated role in mitochondrial function, and its inhibition could protect neurons against calcium overload and cell death in glutamate excitotoxicity.