Monika Gensicka-Kowalewska

Bio: Monika Gensicka-Kowalewska is an academic researcher from Gdańsk University of Technology. The author has contributed to research in topics: Cytotoxicity & Apoptosis. The author has an hindex of 3, co-authored 5 publications receiving 106 citations.

Recent developments in the synthesis and biological activity of acridine/acridone analogues

Abstract: Many people in the world struggle with cancer or bacterial, parasitic, viral, Alzheimer's and other diseases. Therefore, many scientists seek new, more effective, more selective and less toxic drugs. Acridine/acridone derivatives constitute a class of compounds with a broad spectrum of biological activity and are of great interest to scientists. To date, many acridine/acridone analogues have been obtained, which, inter alia, exhibit antitumour (e.g., (1–5)), antimicrobial (e.g., (59)), and antiviral (e.g., (61)) activities and are applicable in the treatment of Alzheimer's disease (e.g., (26)). However, in many cases, their clinical application is limited and excluded because of side effects. In this survey, we describe acridine and acridone derivatives reported since 2013, methods of their synthesis and their potential clinical applications.

Tuftsin - Properties and Analogs.

Abstract: BACKGROUND Immunomodulation is one of the significant therapeutic strategies. It includes both stimulation and suppression of the immune system by a variety of substances called immunomodulators, designed to regulate the immune response of the organism against infections of varying etiology. An example of such a substance is tuftsin (TKPA) 3 (Fig. (1)). In this paper were included tuftsin derivatives, which were described over the years, their together with biological activity and clinical potential. METHODS We reviewed a bibliographic database to gather all the important information about the tuftsin peptide. We have delineated the significant information on the activity of the tetrapeptide itself and its derivatives. Analogs were divided because of their anti-tumor, anti-inflammatory, antimicrobial and anti-viral activity. RESULTS This paper describes eighty-six documents. Thirty-two of them concern on activity of tuftsin in the human organism. The remaining fifty-four describe peptide analogues and their properties, including eleven papers about the tuftsin-based peptides contained in the vaccines, nine papers representing anticancer activity of the tuftsin derivatives, twenty-six about antiinflammatory compounds, and five papers describing the antitumor activity of the tuftsin analogs. CONCLUSION The findings of this review confirm the importance of the tuftsin and their derivatives. Most of these substances showed anti-tumor, anti-inflammatory or antibacterial activities. A large amount of the compounds may find use in vaccines. Tuftsin can also be used to prepare fusion proteins in the treatment of cancer and as carriers of many biologically active substances.

Novel therapeutic compound acridine-retrotuftsin action on biological forms of melanoma and neuroblastoma.

Abstract: As a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes. The cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level. ART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion. Our data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.

Synthesis and Biological Evaluation of Acridine/Acridone Analogs as Potential Anticancer Agents.

Abstract: Background The lack of efficacious therapy for advanced melanoma and neuroblastoma makes new approaches necessary. Therefore, many scientists seek new, more effective, more selective and less toxic anticancer drugs. Objective We propose the synthesis of the new functionalized analogs of 1-nitroacridine/4- nitroacridone connected to tuftsin/retro-tuftsin derivatives as potential anticancer agents. Methods Acridine and acridone analogues were prepared by Ullmann condensation and then cyclization reaction. As a result of nucleophilic substitution reaction 1-nitro-9-phenoxyacridine or 1- chloro-4-nitro-9(10H)-acridone with the corresponding peptides, the planned acridine derivatives (10a-c, 12, 17-a-d, 19) have been obtained. The cytotoxic activity of the newly obtained analogs were evaluated against melanotic (Ma) and amelanotic (Ab) melanoma cell lines and neuroblastoma SH-SY5Y by using the XTT method. Apoptosis and cell cycle were analyzed by flow cytometry. Results Among the investigated analogs compound 12 exhibited the highest potency comparable to dacarbazine action for amelanotic Ab melanoma cells. FLICA test (flurochrome-labeled inhibitors of caspases) showed that this analog significantly increased the content of cells with activated caspases (C+) among both neuroblastoma lines and only Ab melanoma line. Using phosphatidylserine (PS) externalization assay, 12 induced changes in the Ab melanoma plasma membrane structure as the externalization of phosphatidylserine (An+ cells). These changes in neuroblastoma cells were less pronounced. Conclusion Analog 12 could be proposed as the new potential chemotherapeutic against amelanotic melanoma form especially.

Medicinal chemistry of acridine and its analogues.

Abstract: 'Acridine' along with its functional analogue 'Acridone' is the most privileged pharmacophore in medicinal chemistry with diverse applications ranging from DNA intercalators, endonuclease mimics, ratiometric selective ion sensors, and P-glycoprotein inhibitors in countering the multi-drug resistance, enzyme inhibitors, and reversals of neurodegenerative disorders. Their interaction with DNA and ability of selectively identifying numerous biologically useful ions has cemented exploitability of the acridone nucleus in modern day therapeutics. Additionally, most derivatives and salts of acridine are planar, crystalline, and stable displaying a strong fluorescence which, when coupled with their marked bio selectivity and low cytotoxicity, enables the studying and monitoring of several biochemical, metabolic, and pharmacological processes. In this review, a detailed picture covering the important therapeutic aspects of the acridone nucleus and its functional analogues is discussed.

Weakly Coordinating, Ketone-Directed (η5 -Pentamethylcyclopentadienyl)cobalt(III)- and (η5 -Pentamethylcyclopentadienyl)rhodium(III)-Catalyzed C-H Amidation of Arenes: A Route to Acridone Alkaloids.

Abstract: The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks. This amidation proceeded smoothly with a variety of ketones and several amidating partners. The application of the products in the synthesis of various heterocycles, including acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines, was also explored. The total synthesis of acridone-based alkaloids, namely, toddaliopsin A, toddaliopsin D, and arborinine, and the formal synthesis of acronycine and noracronycin were also accomplished by applying this method. A mechanistic study revealed this amidation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease

Abstract: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.