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Signaling pathways and promising small-molecule therapeutic agents for Ischemic Stroke.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-03-02 DOI: 10.1002/cmdc.202400975
Debasis Das, Yimeng Wu, Jian Hong

Stroke is the second highest cause of death and leading cause of disability with the high economic burden worldwide. The incidence of stroke is increasing faster and more prevalent for the global population over age 65. Ischemic stroke (IS) has a higher incidence than hemorrhagic stroke, accounting over 80% of the total incidence of stroke. The incidence rate of ischemic stroke is increasing in all age groups and both sexes. In the modern era, hypertension, high blood pressure and lifestyle are considered as the causes of the disease. Compared to severity, the treatment options for stroke is still limited, mainly thromolytic and thrombectomy therapy. In the past decade, a number of therapeutic agents have been studied for neuroprotection in the acute ischemic stroke to protect the brain from ischemic injury. Several study methods focus to improve neurons functions around the ischemic core and protect from the shock. Many signaling pathways including NF-kB, NrF, Nrf2-Keap1, PI3K/AKT, JAK/STAT signaling pathways are strongly associated for the indication. Controlling the signaling pathways by small molecules potentially improve the neuronal functions. In this article, we review the recent advancement of the drug discovery, controlling signaling pathways by small molecules, and kinase inhibitors in this direction.

{"title":"Signaling pathways and promising small-molecule therapeutic agents for Ischemic Stroke.","authors":"Debasis Das, Yimeng Wu, Jian Hong","doi":"10.1002/cmdc.202400975","DOIUrl":"https://doi.org/10.1002/cmdc.202400975","url":null,"abstract":"<p><p>Stroke is the second highest cause of death and leading cause of disability with the high economic burden worldwide. The incidence of stroke is increasing faster and more prevalent for the global population over age 65. Ischemic stroke (IS) has a higher incidence than hemorrhagic stroke, accounting over 80% of the total incidence of stroke. The incidence rate of ischemic stroke is increasing in all age groups and both sexes. In the modern era, hypertension, high blood pressure and lifestyle are considered as the causes of the disease. Compared to severity, the treatment options for stroke is still limited, mainly thromolytic and thrombectomy therapy. In the past decade, a number of therapeutic agents have been studied for neuroprotection in the acute ischemic stroke to protect the brain from ischemic injury. Several study methods focus to improve neurons functions around the ischemic core and protect from the shock. Many signaling pathways including NF-kB, NrF, Nrf2-Keap1, PI3K/AKT, JAK/STAT signaling pathways are strongly associated for the indication. Controlling the signaling pathways by small molecules potentially improve the neuronal functions. In this article, we review the recent advancement of the drug discovery, controlling signaling pathways by small molecules, and kinase inhibitors in this direction.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400975"},"PeriodicalIF":3.6,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quinoline ATP Synthase Inhibitors with Activity Against Multidrug Resistant Acinetobacter baumannii and Pseudomonas aeruginosa. 对耐多药鲍曼不动杆菌和铜绿假单胞菌具有活性的喹啉 ATP 合成酶抑制剂
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-27 DOI: 10.1002/cmdc.202400952
Katie T Ward, Alexander P L Williams, Angelina L Dennison, Lena Aamir, Darien L Allen, Britza Chavez-Arellano, Toni A Marchlewski, Mars L Zappia, Amanda L Wolfe, P Ryan Steed

The Gram-negative, pathogenic bacteria Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) have been identified as a particular threat due to rising multidrug resistance, and antibiotics with novel mechanisms of action are needed. Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230 ng/mL in vitro, expands the quinoline structure-activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.

{"title":"Quinoline ATP Synthase Inhibitors with Activity Against Multidrug Resistant Acinetobacter baumannii and Pseudomonas aeruginosa.","authors":"Katie T Ward, Alexander P L Williams, Angelina L Dennison, Lena Aamir, Darien L Allen, Britza Chavez-Arellano, Toni A Marchlewski, Mars L Zappia, Amanda L Wolfe, P Ryan Steed","doi":"10.1002/cmdc.202400952","DOIUrl":"https://doi.org/10.1002/cmdc.202400952","url":null,"abstract":"<p><p>The Gram-negative, pathogenic bacteria Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) have been identified as a particular threat due to rising multidrug resistance, and antibiotics with novel mechanisms of action are needed. Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230 ng/mL in vitro, expands the quinoline structure-activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400952"},"PeriodicalIF":3.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of Safe COX-2 Inhibitors: Achieving Reduced Colitis Side Effects through Balanced COX Inhibition.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-27 DOI: 10.1002/cmdc.202500096
Zhiran Ju, Xinlin Zhu, Qin Li, Junhui Wu

The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21d (IC50 value = 1.35 µM, selectivity profile (IC50 (COX-1)/IC50 (COX-2) = 22.34)). In vivo assays demonstrated that 21d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.

{"title":"Discovery of Safe COX-2 Inhibitors: Achieving Reduced Colitis Side Effects through Balanced COX Inhibition.","authors":"Zhiran Ju, Xinlin Zhu, Qin Li, Junhui Wu","doi":"10.1002/cmdc.202500096","DOIUrl":"https://doi.org/10.1002/cmdc.202500096","url":null,"abstract":"<p><p>The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21d (IC50 value = 1.35 µM, selectivity profile (IC50 (COX-1)/IC50 (COX-2) = 22.34)). In vivo assays demonstrated that 21d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500096"},"PeriodicalIF":3.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Career doing STUFF.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-26 DOI: 10.1002/cmdc.202401017
Michael M Hann

In this Guest Editorial for the MedChem Musings series, Mike, Former Senior Research Director at GSK, reflects on a career doing "STUFF": Science, Technology, Useful Functions and Fun. Mike summarises some of the many things he has been involved in throughout his 45 year-career in drug discovery, from which future generations of researchers can hopefully find practical advice and inspiration.

{"title":"A Career doing STUFF.","authors":"Michael M Hann","doi":"10.1002/cmdc.202401017","DOIUrl":"https://doi.org/10.1002/cmdc.202401017","url":null,"abstract":"<p><p>In this Guest Editorial for the MedChem Musings series, Mike, Former Senior Research Director at GSK, reflects on a career doing \"STUFF\": Science, Technology, Useful Functions and Fun. Mike summarises some of the many things he has been involved in throughout his 45 year-career in drug discovery, from which future generations of researchers can hopefully find practical advice and inspiration.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202401017"},"PeriodicalIF":3.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Peptides Corresponding to the Receptor-Binding Domain (RBD) of Several SARS-CoV-2 Variants Of Concern Prevent Recognition of the Human ACE2 Receptor and Consecutive Cell Infections.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-25 DOI: 10.1002/cmdc.202400973
Mandy Schwarze, Alexandra Brakel, Ralf Hoffmann, Andor Krizsan

New strategies are needed to prevent and control upcoming outbreaks of SARS-CoV-2 infections, independent of vaccination. SARS-CoV-2 binds to the human ACE-2 receptor through the receptor binding domain (RBD) of the spike (S) protein, allowing the virus to enter human cells and begin replication. When peptides corresponding to four regions of RBD containing previously reported ACE-2 interaction sites were explored, the sequence 392 to 421, peptide p392wt, bound strongly to ACE-2 and inhibited wild-type RBD binding to ACE-2. Interestingly, p392 peptides corresponding to mutated sequences from different SARS-CoV-2 VOCs, including the current VOC BA.5 and KP.3, bound less strongly to ACE-2, but showed partially better inhibition of the ACE-2 interaction of all tested RBDs. When studied in a SARS-CoV-2 pseudovirus assay, the p392 peptides showed a good inhibition rate of 98.8±8.1 % at a peptide concentration of ~244 μmol/L, while none of the p392 peptides inhibited antibody binding to the RBD, suggesting that peptide treatment is sufficient in the presence of anti-RBD antibodies. Interestingly these peptides were active in the presence of diluted human serum and non-toxic to human cell lines.

{"title":"Peptides Corresponding to the Receptor-Binding Domain (RBD) of Several SARS-CoV-2 Variants Of Concern Prevent Recognition of the Human ACE2 Receptor and Consecutive Cell Infections.","authors":"Mandy Schwarze, Alexandra Brakel, Ralf Hoffmann, Andor Krizsan","doi":"10.1002/cmdc.202400973","DOIUrl":"https://doi.org/10.1002/cmdc.202400973","url":null,"abstract":"<p><p>New strategies are needed to prevent and control upcoming outbreaks of SARS-CoV-2 infections, independent of vaccination. SARS-CoV-2 binds to the human ACE-2 receptor through the receptor binding domain (RBD) of the spike (S) protein, allowing the virus to enter human cells and begin replication. When peptides corresponding to four regions of RBD containing previously reported ACE-2 interaction sites were explored, the sequence 392 to 421, peptide p392wt, bound strongly to ACE-2 and inhibited wild-type RBD binding to ACE-2. Interestingly, p392 peptides corresponding to mutated sequences from different SARS-CoV-2 VOCs, including the current VOC BA.5 and KP.3, bound less strongly to ACE-2, but showed partially better inhibition of the ACE-2 interaction of all tested RBDs. When studied in a SARS-CoV-2 pseudovirus assay, the p392 peptides showed a good inhibition rate of 98.8±8.1 % at a peptide concentration of ~244 μmol/L, while none of the p392 peptides inhibited antibody binding to the RBD, suggesting that peptide treatment is sufficient in the presence of anti-RBD antibodies. Interestingly these peptides were active in the presence of diluted human serum and non-toxic to human cell lines.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400973"},"PeriodicalIF":3.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural insights into Galectin-3 recognition of a selenoglycomimetic.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-25 DOI: 10.1002/cmdc.202401005
Alba Silipo, Maria Pia Lenza, Cristina Di Carluccio, Ferran Nieto-Fabregat, Luciano Pirone, Rita Russo, Sonia Di Gaetano, Domenica Capasso, Alfonso Iadonisi, Michele Saviano, Roberta Marchetti, Emilia Pedone

Chimera-type galectin-3 (Gal-3) is a β-galactoside-binding protein containing a single conserved carbohydrate-recognition domain, crucial in fibrosis and carcinogenesis. Selenium-based Gal-3 inhibitors have emerged as promising therapeutic agents, particularly for treating neoplastic diseases. Among them, a seleno-digalactoside (SeDG) substituted with a benzyl group at position 3 of both saccharide residues (benzyl 3,3'-seleno-digalactoside, SeDG-Bn), attracted considerable attention for its selectivity and potent inhibitory efficacy against Gal-3. NMR spectroscopy and molecular dynamics simulations were combined to investigate the binding of SeDG-Bn to Gal-3 at the molecular level. This approach revealed the recognized epitope, the binding mode within Gal-3 binding pocket, and enabled the generation of a 3D model of the complex. Our findings show that the presence of a single benzyl group establishes hydrophobic contacts with amino acids in Gal-3 b-sheets S2 and S3, crucially enhancing the binding affinity compared to unmodified SeDG. The digalactose backbone orientation in Gal-3 binding site is partially modified by the benzoyl group with respect to complexes with lactosamine and SeDG. These results provide valuable insights into the design of more potent and selective inhibitors for Gal-3, potentially contributing to new therapeutic strategies for conditions such as cancer and fibrosis.

{"title":"Structural insights into Galectin-3 recognition of a selenoglycomimetic.","authors":"Alba Silipo, Maria Pia Lenza, Cristina Di Carluccio, Ferran Nieto-Fabregat, Luciano Pirone, Rita Russo, Sonia Di Gaetano, Domenica Capasso, Alfonso Iadonisi, Michele Saviano, Roberta Marchetti, Emilia Pedone","doi":"10.1002/cmdc.202401005","DOIUrl":"https://doi.org/10.1002/cmdc.202401005","url":null,"abstract":"<p><p>Chimera-type galectin-3 (Gal-3) is a β-galactoside-binding protein containing a single conserved carbohydrate-recognition domain, crucial in fibrosis and carcinogenesis. Selenium-based Gal-3 inhibitors have emerged as promising therapeutic agents, particularly for treating neoplastic diseases. Among them, a seleno-digalactoside (SeDG) substituted with a benzyl group at position 3 of both saccharide residues (benzyl 3,3'-seleno-digalactoside, SeDG-Bn), attracted considerable attention for its selectivity and potent inhibitory efficacy against Gal-3. NMR spectroscopy and molecular dynamics simulations were combined to investigate the binding of SeDG-Bn to Gal-3 at the molecular level. This approach revealed the recognized epitope, the binding mode within Gal-3 binding pocket, and enabled the generation of a 3D model of the complex. Our findings show that the presence of a single benzyl group establishes hydrophobic contacts with amino acids in Gal-3 b-sheets S2 and S3, crucially enhancing the binding affinity compared to unmodified SeDG. The digalactose backbone orientation in Gal-3 binding site is partially modified by the benzoyl group with respect to complexes with lactosamine and SeDG. These results provide valuable insights into the design of more potent and selective inhibitors for Gal-3, potentially contributing to new therapeutic strategies for conditions such as cancer and fibrosis.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202401005"},"PeriodicalIF":3.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of Novel 2-Oxindoles as Compounds with Antiglaucoma Activity.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-23 DOI: 10.1002/cmdc.202400977
Roman O Eremeev, Alexander M Efremov, Daria V Zakharova, Olga V Beznos, Elena V Sokolova, Konstantin Y Kalitin, Olga Y Mukha, Daria V Vinogradova, Ivan M Veselov, Pavel N Shevtsov, Ludmila G Dubova, Denis A Babkov, Alexander A Spasov, Elena F Shevtsova, Natalia A Lozinskaya

Oxindole-based natural indoles analogues retain the rigidity and size of the original indole ring system whilst introducing more 3-dimensionality and potential increased water solubility. We report the first preparation of a diverse series of new melatonin analogues 4, 6, 11, 12 based on 3-hydroxy-2-oxindoles (11) and hydroxy-free 2-oxindoles (4, 6, 12) and evaluated their ability to reduce intraocular pressure as well as their neuroprotective and antioxidant properties. Reductive amination was used to obtain new 5-(benzylamino)-substituted (indolin-3-yl)acetonitriles 11 and (indolin-3-yl)acetic acids 12 with high yields. Compounds 4 a, c, 6 a and 11 a, d, h, j-l demonstrated IOP reduction effect in range 15-27 % similar to the effect of reference compounds melatonin and timolol (12 % and 18 % reduction, respectively). 5-(Benzylamino)-substituted 3-hydroxy-2-oxindoles 11, unlike compounds 4, 6, inhibited lipid peroxidation in range 2.075-13.012 μM. Inhibition of NQO2 associated with antioxidant properties of melatonin was also evaluated for synthesized compounds and it was found that compound 11 h showed the best NQO2 inhibitory activity with an IC50=39 μM (vs. melatonin IC50=64 μM). All synthesized compounds 4, 6, 11, 12 at a concentration of 30 μM do not possess the mitochondrial toxicity. Moreover, no disruption of tubulin polymerization was observed even in the presence of 100 μM of the compounds. Thus, 3-hydroxy-2-oxindole derivatives 11 can be used for drug design of first-in-class antiglaucoma drugs with antioxidant and neuroprotective properties.

{"title":"Discovery of Novel 2-Oxindoles as Compounds with Antiglaucoma Activity.","authors":"Roman O Eremeev, Alexander M Efremov, Daria V Zakharova, Olga V Beznos, Elena V Sokolova, Konstantin Y Kalitin, Olga Y Mukha, Daria V Vinogradova, Ivan M Veselov, Pavel N Shevtsov, Ludmila G Dubova, Denis A Babkov, Alexander A Spasov, Elena F Shevtsova, Natalia A Lozinskaya","doi":"10.1002/cmdc.202400977","DOIUrl":"10.1002/cmdc.202400977","url":null,"abstract":"<p><p>Oxindole-based natural indoles analogues retain the rigidity and size of the original indole ring system whilst introducing more 3-dimensionality and potential increased water solubility. We report the first preparation of a diverse series of new melatonin analogues 4, 6, 11, 12 based on 3-hydroxy-2-oxindoles (11) and hydroxy-free 2-oxindoles (4, 6, 12) and evaluated their ability to reduce intraocular pressure as well as their neuroprotective and antioxidant properties. Reductive amination was used to obtain new 5-(benzylamino)-substituted (indolin-3-yl)acetonitriles 11 and (indolin-3-yl)acetic acids 12 with high yields. Compounds 4 a, c, 6 a and 11 a, d, h, j-l demonstrated IOP reduction effect in range 15-27 % similar to the effect of reference compounds melatonin and timolol (12 % and 18 % reduction, respectively). 5-(Benzylamino)-substituted 3-hydroxy-2-oxindoles 11, unlike compounds 4, 6, inhibited lipid peroxidation in range 2.075-13.012 μM. Inhibition of NQO2 associated with antioxidant properties of melatonin was also evaluated for synthesized compounds and it was found that compound 11 h showed the best NQO2 inhibitory activity with an IC<sub>50</sub>=39 μM (vs. melatonin IC<sub>50</sub>=64 μM). All synthesized compounds 4, 6, 11, 12 at a concentration of 30 μM do not possess the mitochondrial toxicity. Moreover, no disruption of tubulin polymerization was observed even in the presence of 100 μM of the compounds. Thus, 3-hydroxy-2-oxindole derivatives 11 can be used for drug design of first-in-class antiglaucoma drugs with antioxidant and neuroprotective properties.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400977"},"PeriodicalIF":3.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cerium(IV)-catalyzed allylic oxidation of 3-sulfolene: An efficient tool for the synthesis of 4-substituted sulfol-2-enes with antiproliferative activity.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-23 DOI: 10.1002/cmdc.202500010
Elżbieta Łastawiecka, Magdalena Mizerska-Kowalska, Adrianna Sławińska-Brych, Karolina Anna Mrozik, Barbara Zdzisińska

Cyclic sulfones play an important role in the field of drug discovery and design due to their valuable properties and their broad range of applications. Herein, we report an efficient cerium(IV)-catalyzed allylic oxidation of a simple 3-sulfolene. This process provides a straightforward and facile approach to sulfol-2-en-4-one, a versatile synthetic intermediate. Notably, this study represents the first instance of cerium catalysis employed in allylic oxidation. Furthermore, we demonstrated the transformation of sulfol-2-en-4-one into 4-substituted sulfol-2-enes with therapeutic applications. In silico analysis performed using the SwissAdme tool indicated that the obtained 4-amine (7a - 7d) and 4-carbamate (9a and 9b) derivatives of sulfol-2-en-4-one met the rules imposed on small-molecule drugs. Moreover, these compounds inhibited the proliferation (MTT assay) of colon cancer and osteosarcoma cells. Notably, compounds 7b and 7c, which exhibited the best selectivity index (ratio of IC50 calculated for normal and cancer cells), induced cell cycle arrest and apoptosis (flow cytometry analysis). Considering the present results, the cerium-catalyzed allylic oxidation of sulfol-3-ene proves to be an efficient and practical method for synthesizing sulfol-2-en-4-one, a versatile chemical synthon for developing sulfolane derivatives, including those with promising anticancer potential.

{"title":"Cerium(IV)-catalyzed allylic oxidation of 3-sulfolene: An efficient tool for the synthesis of 4-substituted sulfol-2-enes with antiproliferative activity.","authors":"Elżbieta Łastawiecka, Magdalena Mizerska-Kowalska, Adrianna Sławińska-Brych, Karolina Anna Mrozik, Barbara Zdzisińska","doi":"10.1002/cmdc.202500010","DOIUrl":"https://doi.org/10.1002/cmdc.202500010","url":null,"abstract":"<p><p>Cyclic sulfones play an important role in the field of drug discovery and design due to their valuable properties and their broad range of applications. Herein, we report an efficient cerium(IV)-catalyzed allylic oxidation of a simple 3-sulfolene. This process provides a straightforward and facile approach to sulfol-2-en-4-one, a versatile synthetic intermediate. Notably, this study represents the first instance of cerium catalysis employed in allylic oxidation. Furthermore, we demonstrated the transformation of sulfol-2-en-4-one into 4-substituted sulfol-2-enes with therapeutic applications. In silico analysis performed using the SwissAdme tool indicated that the obtained 4-amine (7a - 7d) and 4-carbamate (9a and 9b) derivatives of sulfol-2-en-4-one met the rules imposed on small-molecule drugs. Moreover, these compounds inhibited the proliferation (MTT assay) of colon cancer and osteosarcoma cells. Notably, compounds 7b and 7c, which exhibited the best selectivity index (ratio of IC50 calculated for normal and cancer cells), induced cell cycle arrest and apoptosis (flow cytometry analysis). Considering the present results, the cerium-catalyzed allylic oxidation of sulfol-3-ene proves to be an efficient and practical method for synthesizing sulfol-2-en-4-one, a versatile chemical synthon for developing sulfolane derivatives, including those with promising anticancer potential.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500010"},"PeriodicalIF":3.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of CCR8 Antagonist IDOR-1136-5177 for the Treatment of Cancer.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-23 DOI: 10.1002/cmdc.202400968
Stefan Diethelm, Luboš Remeň, Hamed Aissaoui, Cédric Leroy, Alexia Chavanton-Arpel, Luca Docci, Swen Seeland, François Lehembre, Olivier Corminboeuf

CCR8 is a GPCR mainly expressed in tumor-infiltrating T-regulatory cells (Treg) and high CCR8 expression is associated with poor prognosis in cancer. CCR8 and its ligand CCL1 may be involved in Treg recruitment, conversion and/or immunosuppressive function. Recently, pharmacological inhibition of CCR8 in mouse models has been reported to result in tumor regression and small molecule inhibitors of CCR8 have entered the clinic. Aiming to find a new class of CCR8 antagonists, a high throughput screen (HTS) of the Idorsia compound library was performed. HTS hits with a promising profile were identified and subsequent characterization revealed hERG as a key parameter that required further optimization. We reasoned that a strategy focused on discrete structural modifications would offer significant potential to reduce hERG inhibition. The lead optimization campaign we report led to the identification of compound 52 (IDOR-1136-5177), a highly potent CCR8 antagonist representing a new chemical class of CCR8 inhibitors with excellent in vitro and in vivo properties.

CCR8是一种GPCR,主要表达于肿瘤浸润性T调节细胞(Treg),CCR8的高表达与癌症的不良预后有关。CCR8及其配体CCL1可能参与了Treg的招募、转化和/或免疫抑制功能。最近,有报道称在小鼠模型中对 CCR8 进行药理抑制可导致肿瘤消退,CCR8 的小分子抑制剂也已进入临床。为了找到一类新的CCR8拮抗剂,我们对Idorsia化合物库进行了高通量筛选(HTS)。HTS 筛选结果表明,hERG 是一个需要进一步优化的关键参数。我们推断,以离散结构修饰为重点的策略将为减少 hERG 抑制提供巨大潜力。我们报告的先导化合物优化活动最终确定了化合物 52(IDOR-1136-5177),它是一种高活性 CCR8 拮抗剂,代表了一类新的 CCR8 抑制剂,具有出色的体外和体内特性。
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引用次数: 0
Novel Sulfonamide-Sydnone Hybrids: Complementary Insight into Anti-Inflammatory Action, Anti-SARS-CoV-2 Activity, Human Serum Albumin Interaction, and in silico Analysis.
IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-02-23 DOI: 10.1002/cmdc.202400697
Igor Resendes Barbosa, Mayara Alves Amorim, Vitor Hélio de Souza Oliveira, Eunice André, Guilherme Pereira Guedes, Otávio Augusto Chaves, Carlos Serpa, Natalia Fintelman-Rodrigues, Carolina Q Sacramento, Thiago Moreno L Souza, Carlos Mauricio R Sant'Anna, Aurea Echevarria

Acute lung injury (ALI) is a severe condition often seen in intensive care unit patients. Due to limited treatment options, ALI is linked to high rates of mortality and morbidity. Bacterial and viral infections are significant contributors to ALI. For instance, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can lead to a strong inflammatory response that may progress to ALI, a leading cause of death in COVID-19 cases. Prior research has demonstrated that sulfonamides and sydnones exhibit anti-inflammatory and antiviral properties, which has led us to develop compounds containing both scaffolds. Most of the new sulfonamide-sydnone hybrids are expected to be orally bioavailable based on in silico ADME predictions. They effectively suppressed the development of ALI in lipopolysaccharide (LPS)-challenged mice and inhibited viral replication in Calu-3 cells, with minimal cytotoxicity in non-infected Calu-3 and Vero E6 cells. Molecular docking investigations indicated some possible viral targets for the action of the sydnones, highlighting the possible interaction with non-structural proteins of SARS-CoV-2. Additionally, combined experimental and theoretical studies indicated that the new compounds can strongly interact with human serum albumin, suggesting a possible extended residence time in the human bloodstream.

急性肺损伤(ALI)是重症监护室病人经常出现的一种严重病症。由于治疗方法有限,ALI 的死亡率和发病率都很高。细菌和病毒感染是导致 ALI 的重要因素。例如,严重急性呼吸系统综合征-冠状病毒-2(SARS-CoV-2)感染可导致强烈的炎症反应,进而发展为 ALI,这是 COVID-19 病例的主要死因。先前的研究表明,磺胺类药物和茚酮类药物具有抗炎和抗病毒特性,这促使我们开发了含有这两种支架的化合物。根据硅学 ADME 预测,大多数新的磺胺类和昔多酮类杂交化合物都具有口服生物利用度。它们能有效抑制脂多糖(LPS)挑战小鼠 ALI 的发生,并抑制 Calu-3 细胞的病毒复制,同时对未感染的 Calu-3 和 Vero E6 细胞的细胞毒性极小。分子对接研究表明了茚满酮可能的一些病毒作用靶点,突出了与 SARS-CoV-2 非结构蛋白的可能相互作用。此外,综合实验和理论研究表明,新化合物能与人体血清白蛋白产生强烈的相互作用,这表明它们在人体血液中的停留时间可能会延长。
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引用次数: 0
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