Search

The object of this study is the process of choosing the appropriate types of reservation of reconnaissance fire systems under the conditions of performing a combat mission. The problem that was solved is the unsuitability of existing scientific and methodological apparatus to substantiate the appropriate type of reservation for reconnaissance and fire systems under specific conditions for performing a combat mission. Possible types of reservation of reconnaissance fire systems have been analyzed. Based on the results of the analysis, appropriate types of reservation were established, in particular, active, unactive, majoritarian sliding, distributed, for subsystems, as well as general reservation. A feature of this analysis is that it was carried out taking into account the peculiarities of the functioning of reconnaissance and fire systems. This makes it possible to eliminate existing problem associated with the complexity of the use of reconnaissance and fire systems in a combat event. The scope of practical use of the results of the proposed analysis is the management processes associated with the creation, layout, and use of reconnaissance and fire systems in military administration bodies. A methodology for determining the appropriate type of reservation of reconnaissance fire systems has been devised. A feature of the proposed procedure is the choice of such a type of reservation that makes it possible to save the resource of elements, provided that the task is completed. The proposed methodology ensures an increase in the stability of the functioning of reconnaissance and fire systems by an average of 20% for the conditions adopted within the limits of the example. The proposed methodology closes the problem part, which concerns the procedure and rules for choosing the appropriate type of reservation. The scope and conditions for the practical use of the proposed methodology are management processes related to the planning and determination of the projected effectiveness of hostilities by military authorities

A method for calculation of coefficients of the impact of factors on the need for specialists of the highest qualification was proposed. The method is based on expert evaluation methods, in particular, on determining the importance, degree of realization, and tendency of factors that affect the need for highly qualified specialists. The method implements the unit of data reliability verification based on the Kendall coefficient of concordance and Pearson criterion. The method applies an original approach to determining the competence of experts, in particular, by taking into consideration self-evaluation, mutual evaluation, and objective evaluation. The proposed method makes it possible to take into account the influence of factors on the need for specialists of the highest qualification with the possibility of forecasting. The totality of factors that influence the need for specialists of the highest qualification and the magnitude of their impact was determined. They were determined by calculating the indicators of each of the criteria regarding importance, realization, and tendency. Determining was carried out using the algorithm for calculating the coefficients of influence of the factors on the need for specialists of the highest qualification. In general, the following groups of factors were determined: conditions of scientific and scientific-pedagogical activity at a certain institution of higher education, the attractiveness of scientific and scientific-pedagogical activity in a certain country (region), development of industry (speciality). A group of 30 experts was selected to determine the numerical values of the factors, which satisfies the condition for achieving a confidence probability of 0.94. The results of the evaluation of expert judgments revealed that the most influential factors are: social protection (0.87), budget for higher education (0.99), remuneration (0.9), and prestige of scientific and pedagogical activities (0.91). The least influential are: the number of primary positions in the area (0.48) and self-realization opportunities at a higher education institution (0.58).

The tandem addition of an amine and a thiol to an aromatic dialdehyde engages a selective three-component assembly of a fluorescent isoindole. While an attractive approach for diversity-based fluorophore discovery, isoindoles are typically unstable and present considerable challenges for their practical utility. We found that introduction of electron-withdrawing substituents into the dialdehyde component affords stable isoindole products in one step with acceptable yields and high purity.

The topic of the article is very relevant, first of all, due to the fact that today the development of the information and telecommunication services market involves almost all areas of people’s life in the field of e-commerce. Until April 2020, it was not possible to purchase a medicinal product online on the territory of the Russian Federation due to the lack of a regulatory legal framework regulating such a mechanism. However, at the moment, the relevant legislation has entered into force, regulating in detail the sale of medicines in a remote format. Taking into account the presented circumstances, it seems to us that the issue of studying new legislative acts in the field of remote sale of medicines on the territory of the Russian Federation is largely being updated. The subject of the article is the mechanism of legal regulation of remote sale of medicines in Russia. The purpose of the study is to identify the problems of legal regulation of the process of remote sale of medicines in the Russian Federation at the present stage. This research is based on a combination of groups of classical general scientific methods (induction, deduction, analysis, synthesis) and a number of special methods of scientific cognition applied directly within the framework of legal science (formal legal, comparative legal and others). Within the framework of the presented article, the authors carried out a conceptual analysis of the features of the legal regulation of the sale of medicines using remote technologies, taking into account the latest changes in legislation. The specifics of remote trade in prescription and over-the-counter drugs, as well as the peculiarities of labeling of medicines on the territory of the Russian Federation, are analyzed. As a result of a comprehensive study of current trends in regulatory regulation and justification of possible methods for improving the systems for issuing electronic prescriptions, as well as mandatory labeling of medicines, a conclusion is made about the possibility of further development of remote trade in medicines in the Russian Federation.

This paper proposes an algorithm to substantiate the need for weapons samples, as well as targeting when using a reconnaissance firing system taking into consideration the peculiarities of functioning of such systems. The algorithm essentially implies streamlining the stages in determining the magnitude of the reduction of the enemy's combat potential and, on its basis, the formation of the need for the number of weapons by type. The algorithm makes it possible to take into consideration the nonlinearity of functions that describe both different types of weapons and targets. In addition, this algorithm is based on a modified method of nonlinear programming (two functions). The modification involves the use of a normalized share of the weight of each target as weight coefficients. This allows for targeting while taking into consideration the established level of the combat potential of an enemy. A procedure for determining the need for samples of weapons and targeting in the use of reconnaissance firing systems has been devised. It was determined that in order to achieve the goal of enemy fire damage, it is not typically necessary to use all weapons samples. In general, the procedure makes it possible to take into consideration the peculiarities of the samples of weapons and their suitability to hit a certain target. That could prevent problems with overspending of resources, failures in the detection-defeat cycle, non-fulfillment (not fully performing) tasks during enemy fire damage. In general, the algorithm and procedure for determining the need for the samples of weapons and targeting when using a reconnaissance firing system testify to devising a methodology for justifying the need for weapons samples and targeting. The performance and adequacy of this procedure have been tested by considering an example of determining the need for weapons samples and targeting and obtaining the result confirmed by the experience in the use of reconnaissance firing systems

Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. Surgery, radiation therapy, chemotherapy, and androgen deprivation therapy are currently the standard treatment options for PCa. These have poor outcomes and result in the development of castration-resistant prostate cancer (CRPC), which is the foremost underlying cause of mortality associated with PCa. Taxanes, diterpene compounds approved to treat hormonal refractory PCa, show poor outcomes in CRPC. Polygodial (PG) is a natural sesquiterpene isolated from water pepper (Persicaria hydropiper), Dorrigo pepper (Tasmannia stipitata), and mountain pepper (Tasmannia lanceolata). Previous reports show that PG has an anticancer effect. Our results show that PG robustly inhibits the cell viability, colony formation, and migration of taxane-resistant CRPC cell lines and induces cell cycle arrest at the G0 phase. A toxicity investigation shows that PG is not toxic to primary human hepatocytes, 3T3-J2 fibroblast co-cultures, and non-cancerous BPH-1 cells, implicating that PG is innocuous to healthy cells. In addition, PG induces oxidative stress and activates apoptosis in drug-resistant PCa cell lines. Our mechanistic evaluation by a proteome profiler–human apoptotic array in PC3-TXR cells shows that PG induces upregulation of cytochrome c and caspase-3 and downregulation of antiapoptotic markers. Western blot analysis reveals that PG activates apoptotic and DNA damage markers in PCa cells. Our results suggest that PG exhibits its anticancer effect by promoting reactive oxygen species generation and induction of apoptosis in CRPC cells.

Fluorescent probes have gained profound use in biotechnology, drug discovery, medical diagnostics, molecular and cell biology. The development of methods for the translation of fluorophores into fluorescent probes continues to be a robust field for medicinal chemists and chemical biologists, alike. Access to new experimental designs has enabled molecular diversification and led to the identification of new approaches to probe discovery. This review provides a synopsis of the recent lessons in modern fluorescent probe discovery.

Triple negative breast cancer (TNBC) has fewer treatment options than other types of invasive breastcancer. Moreover, Epithelial to Mesenchymal Transition (EMT) helps enrichment of cancer stem cells(CSCs) which promotes resistance to chemotherapy. Ophiobolin A (OpA), a drug like small molecule wasrecently found to have anti-CSC properties. Our current study investigated the cell death mechanism(s)induced by OpA in various breast cancer cell lines with respect to epithelial-mesenchymal transition(EMT).The mechanism of cell death elicited by OpA was analyzed by applying inhibitors for specific pathwaysincluding apoptosis, necroptosis and paraptosis and by analyzing markers of cell death using flowcytometry and western blotting. HMLE(R) and HMLE(R)-Twist cell lines were used to assay the role of EMT.The formation of necrosomes was analyzed with exogeneous expression of RIPK3 tagged with greenfluorescence protein (GFP) in HeLa cell line which lacks endogenous RIPK3 expression. The necrosomeformation was identified by formation of puncta using confocal microscopy. Immune compromised SCIDmice were used to analyze the effect of OpA In vivo.The data obtained in the present study indicates that OpA has an increased anticancer effect in TNBCcompared to the estrogen receptor (ER) positive breast cancer cells. Cells having undergone EMT wereshown to have more sensitivity towards OpA when compared to -uninduced cell lines, which is sensitiveto Necrostatin-1, an inhibitor of necroptosis. OpA also diminished the CD44hi/CD24lo population in TNBCcells. However, apoptosis and paraptosis inhibitors failed to rescue cell death which clearly confirms thatOpA induces necroptosis cell death pathway in EMT undergone cells. An increased phosphorylation ofRIPK, a necroptosis protein marker, was observed on OpA treatment compared to the control. OpAtreatment significantly increased puncta TNBC compared to the untreated control cells, furtherconfirming the necroptotic cell death in TNBC. OpA treatment showed a significant tumor regression intumor bearing SCID mice. All together our findings identify that OpA induce necroptosis in EMT-enrichedTNBC. The study further needs an in-depth analysis of involvement of EMT in necroptotic cell death inTNBC.Key words: Triple-negative breast cancer, EMT, Ophiobolin A, Necroptosis, cell deathmechanism Citation Format: Santhalakshmi Ranganathan, Alexander Kornienko, Antonio Evidente, Daniel Romo, Joseph Taube. Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6153.

Indolizines and pyrazolo[1,5-a]pyridines were prepared via [3 + 2]-cycloaddition of pyridinium ylides to 1-chloro-2-nitrostyrenes. The synthesized molecules were evaluated for antiproliferative activities against a BE(2)-C neuroblastoma cell line with several compounds decreasing the viability of cancer cells. Indolizine 9db showed higher potency than that of all-trans-retinoic acid, an approved cancer drug. Mechanistically, it was found to inhibit tubulin polymerization and it is thus proposed that the discovered chemistry can be exploited for the development of novel microtubule-targeting anticancer agents.

Aim: The current report describes the discovery of indole derivatives that synergize with standard antibiotics. Materials & methods: The antibacterial activities were determined using an optimized time–kill method, while viability of mammalian cells was assessed using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: The synergy is observed with methicillin- and vancomycin-resistant Staphylococcus aureus bacterial strains, against which the standard antibiotics show no activities of their own. Our indole derivatives in combination with antibiotics lack toxicity toward mammalian cells, do not promote the evolution of resistance of S. aureus in comparison to clinically established antibiotics, and likely work by permeabilizing bacterial cell membranes. Conclusion: The above-mentioned findings demonstrate the potential clinical applications of our indole derivatives.

Lapachol (1) is a well-studied natural product isolated from plants of the Bignoniaceae family and demonstrates diverse biological effects. Historically, chemical transformation of the lapachol scaffold has yielded new derivatives with impressive biological activity and rich chemical diversity. β-lapachone (2), α-lapachone (3), and 2-acetylfuronaphthoquinone (4) are examples of analogs derived from lapachol that show superior antitumor activity compared with the natural product. In the present study, novel indane carboxylic acid: 2,2-dimethyl-2,3-dihydroindeno[1,2-b]pyran-4,5-dione (9) and methyl 5-hydroxy-2,2-dimethyl-2,3,4,5-tetrahydroindeno[1,2-b]pyran-5-carboxylate (10) and naphthoquinone derivatives were synthesized from lapachol with structural similarities to the antitumor lapachol derivatives. The synthesized compounds were evaluated for antiproliferative activities against a panel of human cancer cell lines including in vitro models for neuroblastoma, melanoma, glioblastoma, and non-small cell lung cancer. As expected, the most potent derivatives were those incorporating β-naphthoquinone and α-naphthoquinono[2,3-b]furan skeletons. Many of these compounds possessed nanomolar to single digit micromolar antiproliferative potency. However, the most interesting analog evaluated was the dione 9 with an indeno[1,2-b]pyran skeleton, which demonstrated potent cytotoxic activity. The current investigation identified several new lead compounds that could be used as starting points for anticancer drug discovery., SCOPUS: ar.j, info:eu-repo/semantics/published

It has become increasingly apparent that high-diversity chemical reactions play a significant role in the discovery of bioactive small molecules. Here, we describe an expanse of this paradigm, combining a ‘target-guided synthesis’ concept with Paal–Knorr chemistry applied to the preparation of fluorescent ligands for human prostaglandin-endoperoxide synthase (COX-2).

A chemoenzymatic convergent synthesis of 10-benzyloxy narciclasine from bromobenzene was accomplished in 16 steps. The key transformations included toluene dioxygenase-mediated hydroxylation, nitroso Diels-Alder reaction and intramolecular Heck cyclization. The unnatural derivative of narciclasine was subjected to biological evaluation and its activity was compared to other C-10 and C-7 compounds prepared previously.

Haemanthus humilis Jacq., an indigenous South African Amaryllidaceae, was studied for the first time for its alkaloid content. From the acid extract of its bulbs, albomaculine, incartine, coccinine and montanine, belonging to the lycorine-, homolycorine- and isoquinoline-type alkaloids respectively, were isolated. Coccinine was the main metabolite (1.49 g/kg) and to the best of our knowledge H. humilis is to date the best natural source of this alkaloid. It is noteworthy that this Amaryllidaceae does not synthesize lycorine, the main and most common alkaloid produced by this plant genus. All the isolated alkaloids were bio-assayed for their anticancer activity against a panel of six human cancer cell lines, with coccinine evaluated for the first time. The results showed that coccinine and montanine have significant activity at low micromolar concentrations.

Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O-2) but also remarkably in hypoxic conditions (1% O-2). In vivo, low toxicity was observed at a dose of 1 mg.kg(-1) when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft.

The epithelial-mesenchymal transition (EMT) enables the dissociation of cancer cells from the primary tumor by facilitating tolerance to lack of cell-adhesion, decreasing cellular division and increasing motility of individual cells, which leads to an invasive phenotype that links EMT to metastasis. Furthermore, EMT results in the acquisition of stem-cell markers and an increased ability to initiate tumor growth, supporting the concept that EMT may contribute to the development of a small, persistent sub-population of the tumor called cancer stem cells (CSCs). Cells that have undergone EMT have characteristically suppressed cell cycles, making them resistant to commonly used chemotherapies that target DNA replication or microtubule dynamics, processes essential to replicating cells. Nonspecific treatments can also rely on inducing apoptotic cell death; however, recent debates challenge the efficacy of apoptosis in solid tumors, citing high rates of acquired resistance. Utilizing a compound that induces alternative cell death, namely paraptosis, becomes attractive when these other treatments fail. Relying on an activated gene expression program, paraptosis results in the swelling of the mitochondria and endoplasmic reticulum and Apaf-1-independent alternative caspase-9 activity. Treating with paraptosis-inducing compounds such as Ophiobolin A (OpA) specifically targets otherwise-insensitive CSC and EMT cells to re-sensitize bulk tumor populations to chemotherapies. We describe EMT as a key driver of enhanced sensitivity to paraptosis-induced cell death following short-term treatment with OpA or other paraptosis-inducing compounds. Further, paraptosis selectively eliminates the CSC sub-population by reducing stem cell activity and highlights the potential of this pathway in breast cancer treatment. Citation Format: Reisenauer K, Tao Y, Ingros A, Philip T, Evidente A, Kornienko A, Romo D, Taube J. Epithelial-mesenchymal transition sensitizes breast cancer cells to paraptosis-mediated cell death via the fungus-derived sesterpenoid, Ophiobolin A [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-10.

The epithelial–mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

The fungal metabolite sphaeropsidin A (SphA) has been recognised for its promising cytotoxicity, particularly towards apoptosis- and multidrug-resistant cancers. Owing to its intriguing activity, the development of SphA as a potential anticancer agent has been pursued. However, this endeavour is compromised since SphA exhibits poor physicochemical stability under physiological conditions. Herein, SphA's instability in biological media was explored utilizing LC-MS. Notably, the degradation tendency was found to be markedly enhanced in the presence of amino acids in the cell medium utilized. Furthermore, the study investigated the presence of degradation adducts, including the identification, isolation and structural elucidation of a major degradation metabolite, (4R)-4,4′,4′-trimethyl-3′-oxo-4-vinyl-4′,5′,6′,7′-tetrahydro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2-ene-2-carboxylic acid. Considering the reduced cytotoxic potency of aged SphA solutions, as well as that of the isolated degradation metabolite, the reported antiproliferative activity has been attributed primarily to the parent compound (SphA) and not its degradation species. The fact that SphA continues to exhibit remarkable bioactivity, despite being susceptible to degradation, motivates future research efforts to address the challenges associated with this instability impediment., SCOPUS: ar.j, info:eu-repo/semantics/published

We discovered a reaction of nitroalkanes with 2-hydrazinylquinolines, 2-hydrazinylpyridines and bis-2,4-dihydrazinylpyrimidines in polyphosphoric acid (PPA) affording 1,2,4-triazolo[4,3-a]quinolines, 1,2,4-triazolo[4,3-a]pyridines and bis[1,2,4]triazolo[4,3-a:4′,3′-c]pyrimidines, respectively. The reaction expands the scope of heterocyclic annulations involving phosphorylated nitronates, believed to be the electrophilic intermediates formed from nitroalkanes in PPA. Several of the synthesized triazoles showed promising anticancer activity by inducing differentiation in neuroblastoma cancer cells. Due to the urgent need for novel differentiation agents for neuroblastoma therapy, this finding warrants further evaluation of this class of compounds against neuroblastoma.

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapy, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover, prolonged, sub-cytotoxic exposure to OpA is sufficient to reduce migration, sphere formation, and resistance to doxorubicin. OpA is well-tolerated in mice and treatment with OpA alone reduces tumor burden. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

The sesquiterpene polygodial is an agonist of the transient receptor potential vanilloid 1 (TRPV1). Our group recently reported the synthesis and anticancer effects of polygodial and its derivatives, and showed that these compounds retain activity against apoptosis- and multidrug-resistant cancer cells. Herein, we tested the inhibitory effect of these compounds on the activity of the enzyme Na+/K+-ATPase (NKA) from kidney (α1 isoform) and brain (α2 and α3 isoforms) guinea pig extracts. Polygodial (1) displayed a dose-dependent inhibition of both kidney and brain purified NKA preparations, with higher sensitivity for the cerebral isoforms. Polygo-11,12-diol (2) and C11,C12-pyridazine derivative (3) proved to be poor inhibitors. Unsaturated ester (4) and 9-epipolygodial (5) inhibited NKA preparations from brain and kidney, with the same inhibitory potency. Nevertheless, they did not achieve maximum inhibition even at higher concentration. Comparing the inhibitory potency in crude homogenates and purified preparations of NKA, compounds 4 and 5 revealed a degree of selectivity toward the renal enzyme. Kinetic studies showed a non-competitive inhibition for Na+ and K+ by compounds 1, 4 and 5 and for ATP by 1 and 4. However, compound 5 presented a competitive inhibition type. Furthermore, K+-activated p-nitrophenylphosphatase activity of these purified preparations was not inhibited by 1, 4 and 5, suggesting that these compounds acted in the initial phase of the enzyme's catalytic cycle. These findings suggest that the antitumor action of polygodial and its analogues may be linked to their NKA inhibitory properties and reinforce that NKA may be an important target for cancer therapy.

Prostate cancer (PCa) is the second leading cause of death in American men. The chemotherapeutic treatment strategies are generally not effective and can lead to side effects. Hence, there is an urgent need to identify novel chemotherapeutic agents. The aim of this study was to synthesize and evaluate the therapeutic effects of a synthetic analog of polygodial (PG), a pungent constituent abundantly present in mountain pepper, water pepper and dorrigo pepper, on LNCaP PCa cell line and its anti-cancer mechanisms in a preclinical study. We evaluated the anti-cancer potential of the PG analog namely DRP-27 using various assays such as cell viability by MTT assay, anchorage independent growth by soft agar assay, reactive oxygen species generation by 2′,7′-dichlorofluorescein probe-based fluorescence assay, and apoptosis by Annexin-V and TUNEL assays respectively. Western blot analysis was performed to identify the molecular mechanism of DRP-27-induced cell death. Our results showed that DRP-27 significantly inhibited LNCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, DRP-27 potently inhibited anchorage-independent growth of these cells. Flow cytometry, Annexin-V and TUNEL assays confirmed that DRP-27 induces apoptosis in LNCaP cells. DRP-27 also induced the activation of intracellular reactive oxygen species. Western blot analysis revealed that DRP-27 downregulated the expression of survivin, while activating Bax and DNA damage marker pH(2)AX in LNCaP cells. In conclusion, our study suggests that DRP-27 might be an effective anti-cancer agent for PCa.

In a search of small molecules active against apoptosis-resistant cancer cells, a skeletal rearrangement of alkaloid haemanthamine was utilized to generate a series of compounds possessing the alkaloid montanine ring system. The synthesized compounds were found to inhibit proliferation of cancer cells resistant to apoptosis at micromolar concentrations. Selected compounds were also active against patient-derived glioblastoma cells expressing stem-cell markers. This is the first report describing the preparation of synthetic analogues of the montanine-type alkaloids with antiproliferative activity. The compounds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with poor prognoses.

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C–C and C–N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.

The application of new chemical reactions in a biological context has advanced bioconjugation methods for both fundamental research and commercial arenas. Recent adaptations of reactions such as Huisgen 1,3-dipolar or Diels–Alder cycloadditions have enabled the labeling of specific residues in biomolecules by the attachment of molecules carrying azides, alkynes, or strained alkenes. Although these are fundamental tools, there is a need for the discovery of reactions that can label native proteins. We report herein the adaptation of the Paal–Knorr reaction to label lysine residues in proteins via pyrrole linkages.

Growing evidence indicates that protein synthesis is deregulated in cancer onset and progression and targeting this process might be a selective way to combat cancers. While harmine is known to inhibit DYRK1A and intercalate into the DNA, tri-substitution was shown previously to modify its activity profile in favor of protein synthesis inhibition. In this study, we thus evaluated the optimized derivative CM16 in vitro anti-cancer effects unfolding its protein synthesis inhibition activity. Indeed, the growth inhibitory profile of CM16 in the NCI 60-cancer-cell-line-panel correlated with those of other compounds described as protein synthesis inhibitors. Accordingly, CM16 decreased in a time- and concentration-dependent manner the translation of neosynthesized proteins in vitro while it did not affect mRNA transcription. CM16 rapidly penetrated into the cell in the perinuclear region of the endoplasmic reticulum where it appears to target translation initiation as highlighted by ribosomal disorganization. More precisely, we found that the mRNA expression levels of the initiation factors EIF1AX, EIF3E and EIF3H differ when comparing resistant or sensitive cell models to CM16. Additionally, CM16 induced eIF2α phosphorylation. Those effects could explain, at least partly, the CM16 cytostatic anti-cancer effects observed in vitro while neither cell cycle arrest nor DNA intercalation could be demonstrated. Therefore, targeting protein synthesis initiation with CM16 could represent a new promising alternative to current cancer therapies due to the specific alterations of the translation machinery in cancer cells as recently evidenced with respect to EIF1AX and eIF3 complex, the potential targets identified in this present study.

Indolo[3,2-c]quinolones have been efficiently synthesized via an acid-mediated, one-pot, three-component condensation of arylhydrazines, o-aminoacetophenones, and triazines or nitriles. The synthetic application of this method is showcased by the concise synthesis of isocryptolepine alkaloid and a series of its synthetic analogues with demonstrated cancer cell antiproliferative activities.

The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as “chemotaxonomic markers” for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk-derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen-containing compounds. The “promise” of a mollusk-derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk-derived anticancer agents and solutions to their procurement in quantity.

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4' H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Our laboratories have been investigating biological effects of a sesquiterpenoid polygodial and its natural and synthetic analogues. Herein, we report the evaluation of these compounds against the three forms of Trypanosoma cruzi, amastigotes, trypomastigotes and epimastigotes. Although polygodial was found to be poorly active, its natural congener epipolygodial and synthetic Wittig-derived analogues showed low micromolar potency against all three forms of the parasite. Synthetic α,β-unsaturated phosphonate 9 compared favorably with clinically approved drugs benznidazole and nifurtimox, and was effective against trypomastigotes, toward which benznidazole showed no activity.

Our laboratories have been investigating biological effects of a sesquiterpenoid polygodial and its natural and synthetic analogues. Herein, we report the evaluation of these compounds against the three forms of Trypanosoma cruzi, amastigotes, trypomastigotes and epimastigotes. Although polygodial was found to be poorly active, its natural congener epipolygodial and synthetic Wittig-derived analogues showed low micromolar potency against all three forms of the parasite. Synthetic α,β-unsaturated phosphonate 9 compared favorably with clinically approved drugs benznidazole and nifurtimox, and was effective against trypomastigotes, toward which benznidazole showed no activity.

WOS: 000486259300013, A brief up-to-date overview on the isolation, and chemical and biological characterization of new and known alkaloids from different Amaryllidaceae species, including Brunsvigia, Crinum, Cyrtanthus, Narcissus, and Nerine genera, was reported. Furthermore, the isolation and chemical characterization of alkaloids extracted from bulbs of Narcissus tazetta subsp. tazetta L. collected from Mula, Turkey were described., Department of Chemical Sciences of University of Naples Federico II, The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the academic grant from the Department of Chemical Sciences of University of Naples Federico II.