Roberta Rocca, Serena Ascrizzi, Emanuele Liborio Citriniti, Francesca Scionti, Giada Juli, Maria Teresa Di Martino, Daniele Caracciolo, Anna Artese, Pierosandro Tagliaferri, Pierfrancesco Tassone, Katia Grillone, Stefano Alcaro
Resveratrol (RSV) is a nutraceutical compound belonging to the nonflavonoid polyphenol family, whose antioxidants, anti-inflammatory, and antitumoral properties have been widely investigated. The ability of RSV to provide beneficial effects for neurological, cardiovascular, and cancer disorders rekindled the interest to explore the molecular mechanisms behind its pleiotropic effects, which are due to the modulation of coding and noncoding genes involved in many key biological pathways. With a computational approach, including docking studies and thermodynamics calculations followed by 200-ns-long molecular dynamics and a clustering analysis, we hypothesized the stabilizing binding between RSV and G4 structures of telomeric repeat-containing RNA (TERRA), which is a tumor-suppressive long noncoding RNAs (lncRNA) involved in the regulation of telomere maintenance. In vitro studies performed on cellular models of multiple myeloma (MM) strengthened our hypothesis by highlighting that the antiproliferative and apoptotic effect induced by the treatment with RSV is associated with an increase of TERRA transcript and with upregulation of telomeric heterochromatin markers, such as H3K27Me3 and H4K20Me3, and of the hallmark of apoptosis, cleaved-poly(ADP-ribose) polymerase-1. Our results propose innovative insights underlying the multifaceted role of RSV in MM, by pointing out the role of this natural compound in an lncRNA-mediated regulation to counteract cellular immortality.
{"title":"TERRA G-quadruplex stabilization behind the anti-multiple myeloma activity: Novel insights about resveratrol pleiotropic effects","authors":"Roberta Rocca, Serena Ascrizzi, Emanuele Liborio Citriniti, Francesca Scionti, Giada Juli, Maria Teresa Di Martino, Daniele Caracciolo, Anna Artese, Pierosandro Tagliaferri, Pierfrancesco Tassone, Katia Grillone, Stefano Alcaro","doi":"10.1002/ardp.202400269","DOIUrl":"10.1002/ardp.202400269","url":null,"abstract":"<p>Resveratrol (RSV) is a nutraceutical compound belonging to the nonflavonoid polyphenol family, whose antioxidants, anti-inflammatory, and antitumoral properties have been widely investigated. The ability of RSV to provide beneficial effects for neurological, cardiovascular, and cancer disorders rekindled the interest to explore the molecular mechanisms behind its pleiotropic effects, which are due to the modulation of coding and noncoding genes involved in many key biological pathways. With a computational approach, including docking studies and thermodynamics calculations followed by 200-ns-long molecular dynamics and a clustering analysis, we hypothesized the stabilizing binding between RSV and G4 structures of telomeric repeat-containing RNA (TERRA), which is a tumor-suppressive long noncoding RNAs (lncRNA) involved in the regulation of telomere maintenance. In vitro studies performed on cellular models of multiple myeloma (MM) strengthened our hypothesis by highlighting that the antiproliferative and apoptotic effect induced by the treatment with RSV is associated with an increase of TERRA transcript and with upregulation of telomeric heterochromatin markers, such as H3K27Me3 and H4K20Me3, and of the hallmark of apoptosis, cleaved-poly(ADP-ribose) polymerase-1. Our results propose innovative insights underlying the multifaceted role of RSV in MM, by pointing out the role of this natural compound in an lncRNA-mediated regulation to counteract cellular immortality.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141532548","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}
Esraa Mahmoud, Dalia Abdelhamid, Bahaa G. M. Youssif, Hesham A. M. Gomaa, Alaa M. Hayallah, Mohamad Abdel-Aziz
A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50–2.78 and 0.25–2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.
{"title":"Design, synthesis, and antiproliferative activity of new indole/1,2,4-triazole/chalcone hybrids as EGFR and/or c-MET inhibitors","authors":"Esraa Mahmoud, Dalia Abdelhamid, Bahaa G. M. Youssif, Hesham A. M. Gomaa, Alaa M. Hayallah, Mohamad Abdel-Aziz","doi":"10.1002/ardp.202300562","DOIUrl":"10.1002/ardp.202300562","url":null,"abstract":"<p>A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds <b>9a</b> and <b>9e</b> exhibited significant cancer inhibition with GI<sub>50</sub> ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50–2.78 and 0.25–2.81 at the GI<sub>50</sub> level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound <b>9b</b> showed the highest c-MET inhibition (IC<sub>50</sub> = 4.70 nM) compared to foretinib (IC<sub>50</sub> = 2.5 nM). Compound <b>9d</b> showed equipotent activity compared with erlotinib against EGFR (IC<sub>50</sub> = 0.052 µM) and displayed significant c-MET inhibition with an IC<sub>50</sub> value of 4.90 nM.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202300562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kiran Siwach, Priyanka Arya, Lalit Vats, Vikas Sharma, Simone Giovannuzzi, Neera Raghav, Claudiu T. Supuran, Pawan K. Sharma
The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing KI values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (KI = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (KI = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10−7 M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.
报告了 21 种新型苯磺酰胺-3 官能化吡唑-连环 1,2,3 三唑衍生物作为 cathepsin B 和碳酸酐酶双重抑制剂的设计和合成。目标 1,2,3-三唑连环吡唑酯(16)是通过 1,2,3-三唑二酮酯与 4-肼基苯磺酰胺盐酸盐缩合合成的,并进一步转化为相应的羧酸(17)和羧酰胺(18)类似物。体外检测了合成化合物对人碳酸酐酶(hCA)同工酶 I、II、IX 和 XII 的抑制潜力。结果发现,这些化合物对与癌症有关的 hCA IX 和 XII 具有低纳摩尔水平的强效抑制作用,并对细胞膜异构体 hCA I 具有选择性。所有新合成的化合物都对生理上重要的异构体 hCA II 具有强效抑制作用,KI 值介于 0.8 和 561.5 nM 之间。具有 4-氟苯基(KI = 5.2 nM)的酯类衍生物 16c 是 hCA IX 的最强抑制剂,具有 4-甲基取代苯基的羧酰胺衍生物 18b (KI = 2.2 nM)是 hCA XII 的最强抑制剂。新合成的化合物在 10-7 M 浓度下对酪蛋白酶 B 有很强的抑制作用。一般来说,与相应的酯类衍生物(16)和羧酸衍生物(17)相比,羧酰胺衍生物(18)对 cathepsin B 的抑制率更高。此外,还对目标化合物的吸收、分布、代谢、排泄和毒性(ADMET)以及药物相似性进行了研究。
{"title":"Benzenesulfonamides functionalized with triazolyl-linked pyrazoles possess dual cathepsin B and carbonic anhydrase inhibitory action","authors":"Kiran Siwach, Priyanka Arya, Lalit Vats, Vikas Sharma, Simone Giovannuzzi, Neera Raghav, Claudiu T. Supuran, Pawan K. Sharma","doi":"10.1002/ardp.202400114","DOIUrl":"10.1002/ardp.202400114","url":null,"abstract":"<p>The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (<b>16</b>) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (<b>17</b>) and carboxamide (<b>18</b>) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing <i>K</i><sub>I</sub> values ranging between 0.8 and 561.5 nM. The ester derivative <b>16c</b> having 4-fluorophenyl (<i>K</i><sub>I</sub> = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative <b>18b</b> (<i>K</i><sub>I</sub> = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10<sup>−7</sup> M concentration. In general, the carboxamide derivatives (<b>18</b>) showed higher % inhibition as compared with the corresponding ester derivatives (<b>16</b>) and carboxylic acid derivatives (<b>17</b>) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430919","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}
Jie Ling, Jingping Wu, Yuening Cao, Tingting Zhang, Xiujun Cao, Xian Ge, Yilan Liu, Maolin Wang, Bo Ren, Jun Lu
Tetrandrine (TET) is a natural bis-benzylisoquinoline alkaloid isolated from Stephania species with a wide range of biological and pharmacologic activities; it mainly serves as an anti-inflammatory agent or antitumor adjuvant in clinical applications. However, limitations such as prominent hydrophobicity, severe off-target toxicity, and low absorption result in suboptimal therapeutic outcomes preventing its widespread adoption. Nanoparticles have proven to be efficient devices for targeted drug delivery since drug-carrying nanoparticles can be passively transported to the tumor site by the enhanced permeability and retention (EPR) effects, thus securing a niche in cancer therapies. Great progress has been made in nanocarrier construction for TET delivery due to their outstanding advantages such as increased water-solubility, improved biodistribution and blood circulation, reduced off-target irritation, and combinational therapy. Herein, we systematically reviewed the latest advancements in TET-loaded nanoparticles and their respective features with the expectation of providing perspective and guidelines for future research and potential applications of TET.
{"title":"Advances in nano-preparations for improving tetrandrine solubility and bioavailability","authors":"Jie Ling, Jingping Wu, Yuening Cao, Tingting Zhang, Xiujun Cao, Xian Ge, Yilan Liu, Maolin Wang, Bo Ren, Jun Lu","doi":"10.1002/ardp.202400274","DOIUrl":"10.1002/ardp.202400274","url":null,"abstract":"<p>Tetrandrine (TET) is a natural bis-benzylisoquinoline alkaloid isolated from <i>Stephania</i> species with a wide range of biological and pharmacologic activities; it mainly serves as an anti-inflammatory agent or antitumor adjuvant in clinical applications. However, limitations such as prominent hydrophobicity, severe off-target toxicity, and low absorption result in suboptimal therapeutic outcomes preventing its widespread adoption. Nanoparticles have proven to be efficient devices for targeted drug delivery since drug-carrying nanoparticles can be passively transported to the tumor site by the enhanced permeability and retention (EPR) effects, thus securing a niche in cancer therapies. Great progress has been made in nanocarrier construction for TET delivery due to their outstanding advantages such as increased water-solubility, improved biodistribution and blood circulation, reduced off-target irritation, and combinational therapy. Herein, we systematically reviewed the latest advancements in TET-loaded nanoparticles and their respective features with the expectation of providing perspective and guidelines for future research and potential applications of TET.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502508","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}
Amol A. Nagargoje, Tejshri R. Deshmukh, Mubarak H. Shaikh, Vijay M. Khedkar, Bapurao B. Shingate
Monocarbonyl analogs of curcumin (MACs) represent structurally modified versions of curcumin. The existing literature indicates that MACs exhibit enhanced anticancer properties compared with curcumin. Numerous research articles in recent years have emphasized the significance of MACs as effective anticancer agents. This review focuses on the latest advances in the anticancer potential of MACs, from 2014 to 2024, including discussions on their mechanism of action, structure–activity relationship (SAR), and in silico molecular docking studies.
{"title":"Anticancer perspectives of monocarbonyl analogs of curcumin: A decade (2014–2024) review","authors":"Amol A. Nagargoje, Tejshri R. Deshmukh, Mubarak H. Shaikh, Vijay M. Khedkar, Bapurao B. Shingate","doi":"10.1002/ardp.202400197","DOIUrl":"10.1002/ardp.202400197","url":null,"abstract":"<p>Monocarbonyl analogs of curcumin (MACs) represent structurally modified versions of curcumin. The existing literature indicates that MACs exhibit enhanced anticancer properties compared with curcumin. Numerous research articles in recent years have emphasized the significance of MACs as effective anticancer agents. This review focuses on the latest advances in the anticancer potential of MACs, from 2014 to 2024, including discussions on their mechanism of action, structure–activity relationship (SAR), and in silico molecular docking studies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416893","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}
Jörg Haupenthal, Muhammad Rafehi, Andreas M. Kany, Anne Lespine, Katja Stefan, Anna K. H. Hirsch, Sven Marcel Stefan
Energy-coupling factor transporters (ECFTs) are membrane-bound ATP-binding cassette (ABC) transporters in prokaryotes that are found in pathogens against which novel antibiotics are urgently needed. To date, just 54 inhibitors of three molecular-structural classes with mostly weak inhibitory activity are known. Target repurposing is a strategy that transfers knowledge gained from a well-studied protein family to under-studied targets of phylogenetic relation. Forty-eight human ABC transporters are known that may harbor structural motifs similar to ECFTs to which particularly multitarget compounds may bind. We assessed 31 multitarget compounds which together target the entire druggable human ABC transporter proteome against ECFTs, of which nine showed inhibitory activity (hit rate 29.0%) and four demonstrated moderate to strong inhibition of an ECFT (IC50 values between 4.28 and 50.2 µM) as well as antibacterial activity against ECFT-expressing Streptococcus pneumoniae. Here, ivermectin was the most potent candidate (MIC95: 22.8 µM), and analysis of five ivermectin derivatives revealed moxidectin as one of the most potent ECFT-targeting antibacterial agents (IC50: 2.23 µM; MIC95: 2.91 µM). Distinct molecular-structural features of avermectins and derivatives as well as the differential biological response of the hit compounds in general provided first indications with respect to the structure–activity relationships and mode of action, respectively.
{"title":"Target repurposing unravels avermectins and derivatives as novel antibiotics inhibiting energy-coupling factor transporters (ECFTs)","authors":"Jörg Haupenthal, Muhammad Rafehi, Andreas M. Kany, Anne Lespine, Katja Stefan, Anna K. H. Hirsch, Sven Marcel Stefan","doi":"10.1002/ardp.202400267","DOIUrl":"10.1002/ardp.202400267","url":null,"abstract":"<p>Energy-coupling factor transporters (ECFTs) are membrane-bound ATP-binding cassette (ABC) transporters in prokaryotes that are found in pathogens against which novel antibiotics are urgently needed. To date, just 54 inhibitors of three molecular-structural classes with mostly weak inhibitory activity are known. Target repurposing is a strategy that transfers knowledge gained from a well-studied protein family to under-studied targets of phylogenetic relation. Forty-eight human ABC transporters are known that may harbor structural motifs similar to ECFTs to which particularly multitarget compounds may bind. We assessed 31 multitarget compounds which together target the entire druggable human ABC transporter proteome against ECFTs, of which nine showed inhibitory activity (hit rate 29.0%) and four demonstrated moderate to strong inhibition of an ECFT (IC<sub>50</sub> values between 4.28 and 50.2 µM) as well as antibacterial activity against ECFT-expressing <i>Streptococcus pneumoniae</i>. Here, ivermectin was the most potent candidate (MIC<sub>95</sub>: 22.8 µM), and analysis of five ivermectin derivatives revealed moxidectin as one of the most potent ECFT-targeting antibacterial agents (IC<sub>50</sub>: 2.23 µM; MIC<sub>95</sub>: 2.91 µM). Distinct molecular-structural features of avermectins and derivatives as well as the differential biological response of the hit compounds in general provided first indications with respect to the structure–activity relationships and mode of action, respectively.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}