Khaled A N Abusharkh, Ferah Comert Onder, Venhar Çınar, Alper Onder, Merve Sıkık, Zuhal Hamurcu, Bulent Ozpolat, Mehmet Ay
The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC50 values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.
{"title":"Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies.","authors":"Khaled A N Abusharkh, Ferah Comert Onder, Venhar Çınar, Alper Onder, Merve Sıkık, Zuhal Hamurcu, Bulent Ozpolat, Mehmet Ay","doi":"10.1002/ardp.202400504","DOIUrl":"https://doi.org/10.1002/ardp.202400504","url":null,"abstract":"<p><p>The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC<sub>50</sub> values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to the serious gastrointestinal side effects associated with prolonged use of current anti-inflammatory therapies, various strategies such as the regulation of nitric oxide (NO) and prostaglandin E2 (PGE2) production have been explored in the field of anti-inflammatory drug development. In this study, a series of disubstituted 1,3,4-oxadiazoles (3a-f and 4a-f) and their cyclized 1,2,4-triazole derivatives (5a-e and 6a-e) were synthesized and tested for their NO, PGE2, and interleukin-6 (IL-6) releasing inhibition ability. All of the compounds were observed to reduce lipopolysaccharide (LPS)-induced nitrite production in a concentration-dependent manner. Moreover, compounds 3b (50 μM) and 6d (1 μM) exhibited 63% and 49% inhibition, respectively, while indomethacin showed 52% at 100 μM. Based on a preliminary NO inhibition assay, 10 of the compounds (3a, 3b, 3e, 4b, 4d, 6a-e) were selected to be evaluated for in vitro PGE2, IL-6, and inducible nitric oxide synthase (iNOS) inhibition. Notably, compound 6d proved to be the most active of the series with the lowest dose (1 µM), in comparison to the other further tested compounds (5-100 µM) and the reference drug indomethacin (100 µM). The inhibitory activity of the compounds was supported by docking simulations into the binding site of the iNOS protein receptor (Protein Data Bank [PDB]ID: 3E7G). The data showing that 4d reduced iNOS levels the most can be explained by the H-bond with Tyr347 through oxadiazole and π-halogen interactions through the p-bromo, in addition to aromatic interactions with protoporphyrin IX.
{"title":"iNOS/PGE<sub>2</sub> inhibitors as a novel template for analgesic/anti-inflammatory activity: Design, synthesis, in vitro biological activity and docking studies.","authors":"Ayca Erdogan, Yagmur Ozhan, Hande Sipahi, Enise Ece Gurdal, Wolfgang Sippl, Meric Koksal","doi":"10.1002/ardp.202400238","DOIUrl":"https://doi.org/10.1002/ardp.202400238","url":null,"abstract":"<p><p>Due to the serious gastrointestinal side effects associated with prolonged use of current anti-inflammatory therapies, various strategies such as the regulation of nitric oxide (NO) and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) production have been explored in the field of anti-inflammatory drug development. In this study, a series of disubstituted 1,3,4-oxadiazoles (3a-f and 4a-f) and their cyclized 1,2,4-triazole derivatives (5a-e and 6a-e) were synthesized and tested for their NO, PGE<sub>2</sub>, and interleukin-6 (IL-6) releasing inhibition ability. All of the compounds were observed to reduce lipopolysaccharide (LPS)-induced nitrite production in a concentration-dependent manner. Moreover, compounds 3b (50 μM) and 6d (1 μM) exhibited 63% and 49% inhibition, respectively, while indomethacin showed 52% at 100 μM. Based on a preliminary NO inhibition assay, 10 of the compounds (3a, 3b, 3e, 4b, 4d, 6a-e) were selected to be evaluated for in vitro PGE<sub>2</sub>, IL-6, and inducible nitric oxide synthase (iNOS) inhibition. Notably, compound 6d proved to be the most active of the series with the lowest dose (1 µM), in comparison to the other further tested compounds (5-100 µM) and the reference drug indomethacin (100 µM). The inhibitory activity of the compounds was supported by docking simulations into the binding site of the iNOS protein receptor (Protein Data Bank [PDB]ID: 3E7G). The data showing that 4d reduced iNOS levels the most can be explained by the H-bond with Tyr347 through oxadiazole and π-halogen interactions through the p-bromo, in addition to aromatic interactions with protoporphyrin IX.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure–activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.
{"title":"Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents","authors":"Jingchuan Wu, Xiaohong Lai, Yinyong Zhang, Yuzhu Li, Shuai Huang, Lin Chen, Xianli Zhou","doi":"10.1002/ardp.202400528","DOIUrl":"https://doi.org/10.1002/ardp.202400528","url":null,"abstract":"Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds <b>5a</b>, <b>5c</b>, <b>5e</b>, <b>6</b>, and <b>15j</b> addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds <b>5a</b> and <b>5c</b> having ED<sub>50</sub> values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound <b>5e</b> was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure–activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Berluti, Fady Baselious, Sven Hagemann, Sebastian Hilscher, Matthias Schmidt, Stefan Hüttelmaier, Mike Schutkowski, Wolfgang Sippl, Hany S. Ibrahim
Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, −2, and −3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC50 values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.
{"title":"Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells","authors":"Francesco Berluti, Fady Baselious, Sven Hagemann, Sebastian Hilscher, Matthias Schmidt, Stefan Hüttelmaier, Mike Schutkowski, Wolfgang Sippl, Hany S. Ibrahim","doi":"10.1002/ardp.202400437","DOIUrl":"https://doi.org/10.1002/ardp.202400437","url":null,"abstract":"Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, −2, and −3. Compounds <b>12b</b>, <b>15b</b>, and <b>15i</b> were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC<sub>50</sub> values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mild cognitive impairment (MCI) is a neurodegenerative condition that is clinically prevalent among the elderly. EGB761 is widely recognized for its promising therapeutic properties in both the prevention and treatment of neurodegenerative disorders. The aim of this study was to investigate the effects of EGB761 in MCI and the underlying molecular mechanism. Four‐month‐old SAMP8 mice were used as an in vivo MCI model, and BV2 microglial cells were treated with β‐amyloid (Aβ) 1–42 to establish an in vitro model. First, the cognitive function was evaluated by the Morris water maze. Then, Aβ levels were measured by enzyme‐linked immunosorbent assay. Finally, the underlying molecular mechanism was investigated both in vivo and in vitro. It was found that EGB761 treatment improved the cognitive impairment of SAMP8 mice. In addition, EGB761 inhibited NOD‐like receptor protein 3 inflammasome‐mediated pyroptosis‐related mRNAs and proteins and reduced pyroptosis markers, including gasdermin D fluorescence intensity, propidium iodide‐positive cell count, and the lactate dehydrogenase content. Furthermore, EGB761 inhibited extrinsic and intrinsic apoptosis. Thus, EGB761 had protective effects against pyroptosis and apoptosis in BV2 microglial cells induced by Aβ1‐42 and SAMP8 mice.
{"title":"EGB761 ameliorates mild cognitive impairment by inhibiting the pyroptosis and apoptosis in both in vivo and in vitro experiments","authors":"Xiaolu Zhang, Yingxin Sun, Yujia Zheng, Ruifeng Zhang, Xu Yan, Huayuan Wei, Lin Yang, Xijuan Jiang","doi":"10.1002/ardp.202400593","DOIUrl":"https://doi.org/10.1002/ardp.202400593","url":null,"abstract":"Mild cognitive impairment (MCI) is a neurodegenerative condition that is clinically prevalent among the elderly. EGB761 is widely recognized for its promising therapeutic properties in both the prevention and treatment of neurodegenerative disorders. The aim of this study was to investigate the effects of EGB761 in MCI and the underlying molecular mechanism. Four‐month‐old SAMP8 mice were used as an in vivo MCI model, and BV2 microglial cells were treated with β‐amyloid (Aβ) 1–42 to establish an in vitro model. First, the cognitive function was evaluated by the Morris water maze. Then, Aβ levels were measured by enzyme‐linked immunosorbent assay. Finally, the underlying molecular mechanism was investigated both in vivo and in vitro. It was found that EGB761 treatment improved the cognitive impairment of SAMP8 mice. In addition, EGB761 inhibited NOD‐like receptor protein 3 inflammasome‐mediated pyroptosis‐related mRNAs and proteins and reduced pyroptosis markers, including gasdermin D fluorescence intensity, propidium iodide‐positive cell count, and the lactate dehydrogenase content. Furthermore, EGB761 inhibited extrinsic and intrinsic apoptosis. Thus, EGB761 had protective effects against pyroptosis and apoptosis in BV2 microglial cells induced by Aβ1‐42 and SAMP8 mice.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lara Heidrich, Bastian Brand, Stefan Brackmann, Jan Schäuble, Mohammed Adel Aly, Raphael Reher, Tanja Pommerening, Martin Koch
Resins have been used as remedies since ancient times and various embalming resins have been identified in recent years. In Europe, Mumia vera aegyptiaca, a resinous substance from ancient Egyptian mummies, was even sold in pharmacies as a tonic until the early 20th century. It is difficult to examine the composition of these archeological samples in detail as the well-established analytical techniques, that is, gas chromatography-mass spectrometry or liquid chromatography coupled with tandem mass spectrometry, are destructive and therefore do not allow the analysis of valuable archeological samples. Hence, there is an urgent need for alternative, nondestructive methods for the identification of resin residues. This study aims to explore and compare the use of five spectroscopic methods as an alternative to established analytical procedures. For that, 15 resin samples of known origin and three samples from an Egyptian market were studied. While laser induced-breakdown spectroscopy and terahertz time-domain spectroscopy provide only limited information for resin classification, nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy can be used to classify the resin samples more accurately. Furthermore, photoluminescence/photoluminescence excitation spectroscopy shows a promising potential in combination with its general advantages, such as cost-efficiency, nondestructive nature, and fast data acquisition.
{"title":"Multispectral investigation of natural resins","authors":"Lara Heidrich, Bastian Brand, Stefan Brackmann, Jan Schäuble, Mohammed Adel Aly, Raphael Reher, Tanja Pommerening, Martin Koch","doi":"10.1002/ardp.202400517","DOIUrl":"https://doi.org/10.1002/ardp.202400517","url":null,"abstract":"Resins have been used as remedies since ancient times and various embalming resins have been identified in recent years. In Europe, <i>Mumia vera aegyptiaca</i>, a resinous substance from ancient Egyptian mummies, was even sold in pharmacies as a tonic until the early 20th century. It is difficult to examine the composition of these archeological samples in detail as the well-established analytical techniques, that is, gas chromatography-mass spectrometry or liquid chromatography coupled with tandem mass spectrometry, are destructive and therefore do not allow the analysis of valuable archeological samples. Hence, there is an urgent need for alternative, nondestructive methods for the identification of resin residues. This study aims to explore and compare the use of five spectroscopic methods as an alternative to established analytical procedures. For that, 15 resin samples of known origin and three samples from an Egyptian market were studied. While laser induced-breakdown spectroscopy and terahertz time-domain spectroscopy provide only limited information for resin classification, nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy can be used to classify the resin samples more accurately. Furthermore, photoluminescence/photoluminescence excitation spectroscopy shows a promising potential in combination with its general advantages, such as cost-efficiency, nondestructive nature, and fast data acquisition.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marija Ćorović, Milica Veljković, Ana Milivojević, Anja P. Ivanković, Stevan Blagojević, Rada Pjanović, Dejan Bezbradica
Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat‐M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium‐chain coconut oil‐derived FAAEs exhibited faster diffusion rates compared to sunflower oil‐based FAAEs with long‐side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a lag phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long‐chain esters, the lag phase was prolonged, and the calculated effective diffusion coefficients (Deff) were lower compared to medium‐chain FAAEs. Accordingly, the highest Deff value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil‐derived FAAEs for efficiently delivering vitamin C into the skin.
{"title":"In vitro assessment of skin permeation properties of enzymatically derived oil‐based fatty acid esters of vitamin C","authors":"Marija Ćorović, Milica Veljković, Ana Milivojević, Anja P. Ivanković, Stevan Blagojević, Rada Pjanović, Dejan Bezbradica","doi":"10.1002/ardp.202400538","DOIUrl":"https://doi.org/10.1002/ardp.202400538","url":null,"abstract":"Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat‐M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium‐chain coconut oil‐derived FAAEs exhibited faster diffusion rates compared to sunflower oil‐based FAAEs with long‐side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a <jats:italic>lag</jats:italic> phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long‐chain esters, the <jats:italic>lag</jats:italic> phase was prolonged, and the calculated effective diffusion coefficients (<jats:italic>D</jats:italic><jats:sub>eff</jats:sub>) were lower compared to medium‐chain FAAEs. Accordingly, the highest <jats:italic>D</jats:italic><jats:sub>eff</jats:sub> value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil‐derived FAAEs for efficiently delivering vitamin C into the skin.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Triple‐negative breast cancer (TNBC) treatments, such as DNA‐damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin‐based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (10a–l) reported herein, compound 10j emerged as the most promising, exhibiting notable cytotoxicity with IC50 values of 1.74 and 1.64 µM against MDA‐MB‐231 and MDA‐MB‐468 cells, respectively. The clinically useful drug doxorubicin provided IC50 values of 0.29 and 0.29 µM against MDA‐MB‐231 and MDA‐MB‐468 cells, while artemisinin provided IC50 values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 104 indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.
{"title":"New hydrazide derivatives of N‐amino‐11‐azaartemisinin as promising epidermal growth factor receptor inhibitors for therapeutic development in triple‐negative breast cancer","authors":"Manvika Karnatak, Priyanka Yadav, Komal Rathi, Monika Shukla, Prachi Dugam, Shruthi Suthakaran, Varun Rawat, Mohammad Hassam, Aditi Pandey, Ram Awatar Maurya, Debanjan Sen, Sudhan Debnath, Amitava Das, Achal Mukhija, Ved Prakash Verma","doi":"10.1002/ardp.202400466","DOIUrl":"https://doi.org/10.1002/ardp.202400466","url":null,"abstract":"Triple‐negative breast cancer (TNBC) treatments, such as DNA‐damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin‐based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (10a–l) reported herein, compound 10j emerged as the most promising, exhibiting notable cytotoxicity with IC<jats:sub>50</jats:sub> values of 1.74 and 1.64 µM against MDA‐MB‐231 and MDA‐MB‐468 cells, respectively. The clinically useful drug doxorubicin provided IC<jats:sub>50</jats:sub> values of 0.29 and 0.29 µM against MDA‐MB‐231 and MDA‐MB‐468 cells, while artemisinin provided IC<jats:sub>50</jats:sub> values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 10<jats:sup>4</jats:sup> indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alejandro I. Recio‐Balsells, Renzo Carlucci, Simone Giovannuzzi, Fabrizio Carta, Claudiu T. Supuran, Babu L. Tekwani, Héctor R. Morbidoni, Guillermo R. Labadie
In previous studies, we demonstrated the potent activity of a library of 25 N,N′‐disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against Mycobacterium tuberculosis H37Rv and M. avium, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against M. smegmatis, a non‐pathogenic species, and the non‐tuberculosis mycobacteria M. abscessus, M. kansasii, and M. fortuitum. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against M. tuberculosis (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against M. smegmatis, M. kansasii, and M. fortuitum (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web‐based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.
在之前的研究中，我们证实了一个由 25 个 N,N′-二取代二胺（NNDDA）组成的文库对锥虫和吸虫具有很强的活性。考虑到该化合物库与抗结核化合物 SQ109 的结构相似性及其令人信服的抗寄生虫特性，我们打算将该化合物库重新用于结核病治疗。我们针对结核分枝杆菌 H37Rv 和阿维菌对该化合物库进行了化验，获得了几个 MIC 值低于 10 µM 的化合物。我们还评估了最活跃的类似物对非致病性的 M. smegmatis 以及非结核分枝杆菌 M. abscessus、M. kansasii 和 M. fortuitum 的作用。3c 是该化合物集的主要分枝杆菌化合物，对结核杆菌具有强效活性（最小抑菌浓度 [MIC] = 3.4 µM），对烟肉霉菌、堪萨斯霉菌和脓肿霉菌具有中等活性（MIC 值均为 26.8 µM）。为了揭示其作用机制，我们使用了基于网络的平台 Polypharmacology Browser 2 (PPB2)，获得了作为潜在药物靶点的碳酸酐酶。然而，没有一种化合物显示出实验抑制作用。总之，我们的研究证实了再利用方法的有效性，并强调了 NNDDA 化合物，尤其是类似物 3c 的抗霉菌潜力，为进一步研究奠定了基础。
{"title":"Repurposing antiparasitic N,N′‐aliphatic diamine derivatives as promising antimycobacterial agents","authors":"Alejandro I. Recio‐Balsells, Renzo Carlucci, Simone Giovannuzzi, Fabrizio Carta, Claudiu T. Supuran, Babu L. Tekwani, Héctor R. Morbidoni, Guillermo R. Labadie","doi":"10.1002/ardp.202400597","DOIUrl":"https://doi.org/10.1002/ardp.202400597","url":null,"abstract":"In previous studies, we demonstrated the potent activity of a library of 25 <jats:italic>N,N′</jats:italic>‐disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against <jats:italic>Mycobacterium tuberculosis</jats:italic> H37<jats:italic>Rv</jats:italic> and <jats:italic>M. avium</jats:italic>, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against <jats:italic>M. smegmatis</jats:italic>, a non‐pathogenic species, and the non‐tuberculosis mycobacteria <jats:italic>M. abscessus</jats:italic>, <jats:italic>M. kansasii</jats:italic>, and <jats:italic>M. fortuitum</jats:italic>. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against <jats:italic>M. tuberculosis</jats:italic> (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against <jats:italic>M. smegmatis</jats:italic>, <jats:italic>M. kansasii</jats:italic>, and M<jats:italic>. fortuitum</jats:italic> (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web‐based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Agustina Ibarra, María Julia Ferronato, Valentina Clemente, Anabel Barrientos, Eliana Noelia Alonso, María Eugenia Fermento, Georgina Pamela Coló, María Marta Facchinetti, Alejandro Carlos Curino, Mariela Agotegaray
Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub‐acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3‐aminopropyltriethoxisilane (Si@NH2) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA‐MB‐231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA‐MB‐231 cells. Moreover, none of the SiNPs cause signs of sub‐acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.
{"title":"Amorphous silica nanoparticles exhibit antitumor activity in triple‐negative breast cancer cells","authors":"Agustina Ibarra, María Julia Ferronato, Valentina Clemente, Anabel Barrientos, Eliana Noelia Alonso, María Eugenia Fermento, Georgina Pamela Coló, María Marta Facchinetti, Alejandro Carlos Curino, Mariela Agotegaray","doi":"10.1002/ardp.202400316","DOIUrl":"https://doi.org/10.1002/ardp.202400316","url":null,"abstract":"Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub‐acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3‐aminopropyltriethoxisilane (Si@NH<jats:sub>2</jats:sub>) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA‐MB‐231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA‐MB‐231 cells. Moreover, none of the SiNPs cause signs of sub‐acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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