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Poor efficiency of chemotherapeutics in the eradication of Cancer Stem Cells (CSCs) has been driving the search for more active and specific compounds. In this work, we show how cell density-dependent stage culture profiles can be used in drug development workflows to achieve more robust drug activity (IC50 and EC50) results. Using flow cytometry and light microscopy, we characterized the cytological stage profiles of the HL-60-, A-549-, and HEK-293-derived sublines with a focus on their primitive cell content. We then used a range of cytotoxic substances—C-123, bortezomib, idarubicin, C-1305, doxorubicin, DMSO, and ethanol—to highlight typical density-related issues accompanying drug activity determination. We also showed that drug EC50 and selectivity indices normalized to primitive cell content are more accurate activity measurements. We tested our approach by calculating the corrected selectivity index of a novel chemotherapeutic candidate, C-123. Overall, our study highlights the usefulness of accounting for primitive cell fractions in the assessment of drug efficiency.

The mechanisms of antigen processing and presentation play a crucial role in the recognition and targeting of cancer cells by the immune system. Cancer cells can evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens, creating an immunosuppressive microenvironment, and altering their ability to process and present antigens. This review focuses on the mechanisms of cancer immune evasion with a specific emphasis on the role of antigen presentation machinery. The study of the immunopeptidome, or peptidomics, has provided insights into the mechanisms of cancer immune evasion and has potential applications in cancer diagnosis and treatment. Additionally, manipulating the epigenetic landscape of cancer cells plays a critical role in suppressing the immune response against cancer. Targeting these mechanisms through the use of HDACis, DNMTis, and combination therapies has the potential to improve the efficacy of cancer immunotherapy. However, further research is needed to fully understand the mechanisms of action and optimal use of these therapies in the clinical setting.

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically active compounds. Pyrazine-functionalized carbazole derivative was constructed by coupling 2-amino-5-bromo-3-methylaminepyrazine (ABMAP) into 3 and 6 positions of the carbazole ring. Multiexperimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder, 1 H and 13 C NMR), electrochemical (cyclic voltammetry), and optical techniques, to receive the complete structural analysis, physicochemical (pKa, logP) and biological profile of a new carbazole derivative with acronym 3,6-PIRAMICAR. the interaction ability of the compound studied with potential cellular targets like Calf Thymus DNA (CT-DNA), or BovineSerumAlbumin (BSA) were also taken into account. experiments showed the existence of strong binding, but no DnA or BSA cleavage was observed. the comparative analyzes of compounds anti-Candida action clearly show pH-dependent antifungal activity of 3,6-PIRAMICAR , which was strongly stimulated in the acidic media. Surprisingly, the titled compound turn out to be much more effective (14 times by MIC50; 8 times by MIC; c.a. 4 times by MFC) against Candidakrusei than fluconazole at pH 4. The emergence of multidrug-resistant microorganisms, as well as fungal infectious diseases, is a major global problem, especially for immuno-deficient populations. The development of new antifungal agents in clinical trials is problematic inferior to the incidence of drug resistance, and the available antifungal agents are restricted. Their mechanisms are based on certain characteristics of the fungus in order to avoid biological similarities with the host 1. Fungi in the Candida genus are the most common fungal pathogens which can colonize various host niches (stomach, vagina and oral mucosa) with varying ambient pH range 2-6. Carbazoles and derivatives with carbazole skeleton are currently tested intensively according to their antimicrobial properties which is directly relating with their structure or in more details with anaromatic N-heterocyclic ring inside 7. Carbazole derivatives have been reported to be potential agents against tumor 8 or opportunistic infections of AIDS 9,10. The studies about high active DNA intercalators show the significance of the carbazole structural agents like planarity or aromaticity 11,12. Interestingly, the mentioned parameters are described as responsible for the high affinity of carbazoles substituted at 3,6-or 2,7-positions by amine, amidine, or imidazoline groups to GC or AT-rich sequences of DNA 13,14. However, chemistry of especially di-substituted 3,6-derivatives of carbazole is still not very extensively explored due to problems with synthesis of such compounds. Mainly nitrogen atom was a hot spot for carbazole derivatives 14. The first concept of the studies was to check the basic design structures assumptions to predict pharmaceuticals activity, like presented carbazole functionalized by pyrazines-our previous research objects. Consequently, the confirmation of the possibili...

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related deaths worldwide and is therefore one of the most lethal malignancies. Pyrazole scaffold possesses a wide range of biological and pharmacological activities, which play important roles in medicinal chemistry. The present study reports the synthesis and in vitro biological characterization of nine pyrazoles derived from chalcones as potential anticancer agents for non-small cell lung cancer A-549, H226, and H460 cell lines. Most of the compounds efficiently inhibited the growth of all the tested cancer cell lines at micromolar concentrations. One of the most active compounds (PCH-1) was further evaluated for its effect on cell cycle distribution, apoptosis, migration, epithelial–mesenchymal transition, and oxidative stress. Furthermore, studies on the mechanism of action revealed that PCH-1 disrupts microtubule assembly, leading to cancer cell death. Molecular modeling studies confirmed the potent interaction of PCH-1 with the vinblastine binding site on tubulin. Overall, this study provides novel opportunities to identify anticancer agents in the pyrazole series.