Mateusz Olszewski - Academia.edu (original) (raw)

Papers by Mateusz Olszewski

Human DNA topoisomerases are vital enzymes for DNA replication, transcription, chromatin condensa... more Human DNA topoisomerases are vital enzymes for DNA replication, transcription, chromatin condensation, and maintenance of their structure. Due to this fact inhibition of topoisomerase II is a common approach used in cancer treatment. Carbazole scaffold has a wide range of biological activities and appears as a core in many active compounds. It also plays important role in anticancer research. The present study shows the in vitro biological evaluation of three symmetric carbazole derivatives, substituted with furan or thiophene, as potential antitumor agents. Compounds efficiently inhibited the proliferation of all tested cancer cell lines mostly at nanomolar concentrations. They were further characterized for their effect on cell cycle progression, mitochondria disruption, DNA damage induction, and type of cellular death. Moreover, analysis of their mode of action indicates, that investigated carbazole derivatives inhibit topoisomerase II. Among them, compound 36a exhibited the stro...

Journal of Cancer Research and Clinical Oncology

The mechanisms of antigen processing and presentation play a crucial role in the recognition and ... more 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 i...

Journal of Molecular Structure

The anticancer properties of quinolones is a topic of interest among researchers in the scientifi... more The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the sub-G1 phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study sugges...

Scientific Reports, 2020

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically ac... more 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. Multi-experimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder,1H and13C 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 Bovine Serum Albumin (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 ...

Scientific Reports, Nov 9, 2022

The anticancer properties of quinolones is a topic of interest among researchers in the scientifi... more The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the G 2 /M phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study suggest that tetrahydroquinolinone derivatives bearing a carbonyl group at position 2 could be potential lead compounds to develop anticancer agents for the treatment of lung cancers. Apoptosis or programmed cell death is a basic physiological process that plays a key role in the maintenance of tissue homeostasis. It is genetically regulated as a normal physiological response to many stimuli and is associated with other processes such as aging and embryogenesis. Disorders in apoptosis mechanisms can lead to various diseases, such as cancers. The disability of cancerous cells to keep up the balance between proliferation and death results in the development of abnormal tissue and formation of solid tumors 1,2. Apoptosis is a double-track mechanism that occurs via extrinsic and intrinsic pathways. The extrinsic pathway involves transmembrane death receptor-mediated interactions, whereas the intrinsic pathway is mediated by mitochondria and starts with the binding of BAX/BAK protein to the mitochondrial membrane leading to the release of cytochrome c 3. Both pathways converge at the same point-caspases-regulated execution. The majority of cytostatic drugs used in anticancer therapy cause burdensome side effects in patients; therefore, there is a constant search for novel chemical compounds that are safe. Quinolones are a family of compounds characterized by antibacterial properties. However, research indicates that some of them exhibit potential anticancer properties, especially apoptosis activation. It has been proven that ciprofloxacin, which is the most active fluoroquinolone, can activate apoptosis in breast, bladder, and prostate cancers, colorectal carcinoma, and melanoma. At the molecular level, this chemotherapeutic causes an adverse increase in the concentration of BAX protein which results in differences in the BAX:BCL-2 ratio. It also enhances the expression of p53 protein and activation of caspases 4-8. Another fluoroquinolone, enoxacin, also works by activating apoptosis. It has been shown that programmed cell death is induced in prostate cancer by a significant increase in CASP3 mRNA and cleaved PARP expression as well as mitochondrial depolarization 9. Levofloxacin, which is also a fluoroquinolone, induces apoptosis in breast and lung cancer through a caspase-dependent pathway and mitochondrial disfunction 10. Obviously, several wellknown chemotherapeutic agents from the quinolone family display anticancer properties 11. One of the newer quinolones, voreloxin, which is currently in clinical trials for the treatment of acute myeloid leukemia, shows a high affinity to eukaryotic type II topoisomerase and induces apoptosis through double-strand DNA breaks. Because the stable quinolone core is characterized by a favorable toxicity profile, voreloxin does not generate

Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and... more Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8tetrahydroquinolin-8-yl) N-(3-uorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These ndings suggest that this tetrahydroquinolinone can be an ideal lead compound for drug discovery based on quinone derivatives.

Scientific Reports

Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and... more Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8-tetrahydroquinolin-8-yl) N-(3-fluorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These ...

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellu... more Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered as a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using cellular thermal shift assay. Together with the compound-induced aggregation, human telomerase reverse transcriptase (hTERT) was translocated from the nucleus to the cytoplasm, which su...

Molecules

Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activit... more Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA. Cytotoxicity studies revealed that the compound did not exhibit toxicity toward human dermal keratinocytes, which supported the potential application of 2Cl3HP in clinical use. The study also attempted to establish the possible equilibria occurring in the aqueous solution and, using both theoretical and experimental methods,...

International Journal of Molecular Sciences, 2021

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in an... more Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cance...

Bioconjugate Chemistry, 2018

Proceedings of the 35th European Peptide Symposium, 2018

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related d... more 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 (PCH-1) efficiently inhibited the growth of all the tested cancer cell lines at micromolar concentrations. One of the most active compounds 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 th...

Human DNA topoisomerases are vital enzymes for DNA replication, transcription, chromatin condensa... more Human DNA topoisomerases are vital enzymes for DNA replication, transcription, chromatin condensation, and maintenance of their structure. Due to this fact inhibition of topoisomerase II is a common approach used in cancer treatment. Carbazole scaffold has a wide range of biological activities and appears as a core in many active compounds. It also plays important role in anticancer research. The present study shows the in vitro biological evaluation of three symmetric carbazole derivatives, substituted with furan or thiophene, as potential antitumor agents. Compounds efficiently inhibited the proliferation of all tested cancer cell lines mostly at nanomolar concentrations. They were further characterized for their effect on cell cycle progression, mitochondria disruption, DNA damage induction, and type of cellular death. Moreover, analysis of their mode of action indicates, that investigated carbazole derivatives inhibit topoisomerase II. Among them, compound 36a exhibited the stro...

Journal of Cancer Research and Clinical Oncology

The mechanisms of antigen processing and presentation play a crucial role in the recognition and ... more 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 i...

Journal of Molecular Structure

The anticancer properties of quinolones is a topic of interest among researchers in the scientifi... more The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the sub-G1 phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study sugges...

Scientific Reports, 2020

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically ac... more 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. Multi-experimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder,1H and13C 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 Bovine Serum Albumin (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 ...

Scientific Reports, Nov 9, 2022

The anticancer properties of quinolones is a topic of interest among researchers in the scientifi... more The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the G 2 /M phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study suggest that tetrahydroquinolinone derivatives bearing a carbonyl group at position 2 could be potential lead compounds to develop anticancer agents for the treatment of lung cancers. Apoptosis or programmed cell death is a basic physiological process that plays a key role in the maintenance of tissue homeostasis. It is genetically regulated as a normal physiological response to many stimuli and is associated with other processes such as aging and embryogenesis. Disorders in apoptosis mechanisms can lead to various diseases, such as cancers. The disability of cancerous cells to keep up the balance between proliferation and death results in the development of abnormal tissue and formation of solid tumors 1,2. Apoptosis is a double-track mechanism that occurs via extrinsic and intrinsic pathways. The extrinsic pathway involves transmembrane death receptor-mediated interactions, whereas the intrinsic pathway is mediated by mitochondria and starts with the binding of BAX/BAK protein to the mitochondrial membrane leading to the release of cytochrome c 3. Both pathways converge at the same point-caspases-regulated execution. The majority of cytostatic drugs used in anticancer therapy cause burdensome side effects in patients; therefore, there is a constant search for novel chemical compounds that are safe. Quinolones are a family of compounds characterized by antibacterial properties. However, research indicates that some of them exhibit potential anticancer properties, especially apoptosis activation. It has been proven that ciprofloxacin, which is the most active fluoroquinolone, can activate apoptosis in breast, bladder, and prostate cancers, colorectal carcinoma, and melanoma. At the molecular level, this chemotherapeutic causes an adverse increase in the concentration of BAX protein which results in differences in the BAX:BCL-2 ratio. It also enhances the expression of p53 protein and activation of caspases 4-8. Another fluoroquinolone, enoxacin, also works by activating apoptosis. It has been shown that programmed cell death is induced in prostate cancer by a significant increase in CASP3 mRNA and cleaved PARP expression as well as mitochondrial depolarization 9. Levofloxacin, which is also a fluoroquinolone, induces apoptosis in breast and lung cancer through a caspase-dependent pathway and mitochondrial disfunction 10. Obviously, several wellknown chemotherapeutic agents from the quinolone family display anticancer properties 11. One of the newer quinolones, voreloxin, which is currently in clinical trials for the treatment of acute myeloid leukemia, shows a high affinity to eukaryotic type II topoisomerase and induces apoptosis through double-strand DNA breaks. Because the stable quinolone core is characterized by a favorable toxicity profile, voreloxin does not generate

Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and... more Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8tetrahydroquinolin-8-yl) N-(3-uorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These ndings suggest that this tetrahydroquinolinone can be an ideal lead compound for drug discovery based on quinone derivatives.

Scientific Reports

Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and... more Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8-tetrahydroquinolin-8-yl) N-(3-fluorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These ...

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellu... more Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered as a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using cellular thermal shift assay. Together with the compound-induced aggregation, human telomerase reverse transcriptase (hTERT) was translocated from the nucleus to the cytoplasm, which su...

Molecules

Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activit... more Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA. Cytotoxicity studies revealed that the compound did not exhibit toxicity toward human dermal keratinocytes, which supported the potential application of 2Cl3HP in clinical use. The study also attempted to establish the possible equilibria occurring in the aqueous solution and, using both theoretical and experimental methods,...

International Journal of Molecular Sciences, 2021

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in an... more Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cance...

Bioconjugate Chemistry, 2018

Proceedings of the 35th European Peptide Symposium, 2018

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related d... more 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 (PCH-1) efficiently inhibited the growth of all the tested cancer cell lines at micromolar concentrations. One of the most active compounds 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 th...