Development of Photoswitchable Tethered Ligands that Target the µ-Opioid Receptor
ChemMedChem. 2023 Oct 10:e202300228. doi: 10.1002/cmdc.202300228. Online ahead of print.ABSTRACTConverting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand c...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Ranit Lahmy Harald Huebner Daniel Lachmann Peter Gmeiner Burkhard K önig Source Type: research
The 17 < sup > th < /sup > EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders
This report summarizes the successful event, key lectures given and topics discussed.PMID:37817354 | DOI:10.1002/cmdc.202300464 (Source: ChemMedChem)
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Alessio Ciulli Suzanne O'Connor Chun-Wa Chung Ingo V Hartung Andrea Testa Danette L Daniels Laura H Heitman Source Type: research
Moving out of the CF3-land: synthesis, receptor affinity and in silico studies of NK1-receptor ligands containing pentafluorosulfanyl (SF5) group
ChemMedChem. 2023 Oct 11:e202300315. doi: 10.1002/cmdc.202300315. Online ahead of print.ABSTRACTThe NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5-group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5-containing compounds. All the novel analogues exhibit detectable NK1R bindin...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Katarzyna Witoszka Joanna Matali ńska Aleksandra Misicka Piotr Lipi ński Source Type: research
Discovery of a dual-target inhibitor of CDK7 and HDAC1 that induces apoptosis and inhibits migration in colorectal cancer
In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer stro...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Yao Chen Shuangqian Zhang Zhijia Li Bo Yin Yi Liu Lan Zhang Source Type: research
Protein-Porphyrin Complex Photosensitizers for Anticancer and Antimicrobial Photodynamic Therapies
ChemMedChem. 2023 Oct 11:e202300373. doi: 10.1002/cmdc.202300373. Online ahead of print.ABSTRACTPhotodynamic therapy (PDT) efficiently induces apoptosis through visible-light irradiation of photosensitizers (PSs) within tumors and microbial cells. Porphyrin analogues serve as widely utilized photosensitizing agents with their theranostic abilities being governed by molecular structures and central metal ions. However, these macrocyclic compounds tend to agglutinate and form stacks in aqueous environments, resulting in a loss of photochemical activity. To overcome this limitation, encapsulation within liposomes and polymer ...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Taiga Yamada Teruyuki Komatsu Source Type: research
Development of Photoswitchable Tethered Ligands that Target the µ-Opioid Receptor
ChemMedChem. 2023 Oct 10:e202300228. doi: 10.1002/cmdc.202300228. Online ahead of print.ABSTRACTConverting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand c...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Ranit Lahmy Harald Huebner Daniel Lachmann Peter Gmeiner Burkhard K önig Source Type: research
The 17 < sup > th < /sup > EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders
This report summarizes the successful event, key lectures given and topics discussed.PMID:37817354 | DOI:10.1002/cmdc.202300464 (Source: ChemMedChem)
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Alessio Ciulli Suzanne O'Connor Chun-Wa Chung Ingo V Hartung Andrea Testa Danette L Daniels Laura H Heitman Source Type: research
Discovery of a dual-target inhibitor of CDK7 and HDAC1 that induces apoptosis and inhibits migration in colorectal cancer
In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer stro...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Yao Chen Shuangqian Zhang Zhijia Li Bo Yin Yi Liu Lan Zhang Source Type: research
Protein-Porphyrin Complex Photosensitizers for Anticancer and Antimicrobial Photodynamic Therapies
ChemMedChem. 2023 Oct 11:e202300373. doi: 10.1002/cmdc.202300373. Online ahead of print.ABSTRACTPhotodynamic therapy (PDT) efficiently induces apoptosis through visible-light irradiation of photosensitizers (PSs) within tumors and microbial cells. Porphyrin analogues serve as widely utilized photosensitizing agents with their theranostic abilities being governed by molecular structures and central metal ions. However, these macrocyclic compounds tend to agglutinate and form stacks in aqueous environments, resulting in a loss of photochemical activity. To overcome this limitation, encapsulation within liposomes and polymer ...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Taiga Yamada Teruyuki Komatsu Source Type: research
Moving out of the CF3-land: synthesis, receptor affinity and in silico studies of NK1-receptor ligands containing pentafluorosulfanyl (SF5) group
ChemMedChem. 2023 Oct 11:e202300315. doi: 10.1002/cmdc.202300315. Online ahead of print.ABSTRACTThe NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5-group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5-containing compounds. All the novel analogues exhibit detectable NK1R bindin...
Source: ChemMedChem - October 11, 2023 Category: Chemistry Authors: Katarzyna Witoszka Joanna Matali ńska Aleksandra Misicka Piotr Lipi ński Source Type: research
Design of novel balanced COX inhibitors based on natural anti-inflammatory ascidian metabolites and celecoxib
In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine R...
Source: ChemMedChem - October 10, 2023 Category: Chemistry Authors: Jingjie Fang Ziyi Shang Kumaravel Kaliaperumal Zhiran Ju Fen-Er Chen Source Type: research
Design of novel balanced COX inhibitors based on natural anti-inflammatory ascidian metabolites and celecoxib
In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine R...
Source: ChemMedChem - October 10, 2023 Category: Chemistry Authors: Jingjie Fang Ziyi Shang Kumaravel Kaliaperumal Zhiran Ju Fen-Er Chen Source Type: research
Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents Against Pseudomonas aeruginosa
ChemMedChem. 2023 Oct 8:e202300496. doi: 10.1002/cmdc.202300496. Online ahead of print.ABSTRACTDue to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, pr...
Source: ChemMedChem - October 8, 2023 Category: Chemistry Authors: Casey N Kellogg Bryce A Pugh Isaak M Starr Dhruvi J Parmar A'Zane D Troxler Amanda Wolfe Source Type: research
Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents Against Pseudomonas aeruginosa
ChemMedChem. 2023 Oct 8:e202300496. doi: 10.1002/cmdc.202300496. Online ahead of print.ABSTRACTDue to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, pr...
Source: ChemMedChem - October 8, 2023 Category: Chemistry Authors: Casey N Kellogg Bryce A Pugh Isaak M Starr Dhruvi J Parmar A'Zane D Troxler Amanda Wolfe Source Type: research
Design of 3-phenylcoumarins and 3-thienylcoumarins as potent xanthine oxidase inhibitors: synthesis, biological evaluation and docking studies
ChemMedChem. 2023 Oct 6:e202300400. doi: 10.1002/cmdc.202300400. Online ahead of print.ABSTRACTCoumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3'-Bromophenyl)-5,7-dihydroxycoumarin (compound 11) proved to be the most potent XO inhibitor, with an IC50 of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound 11 and compound 5 [3-(4'-bromothien-2'-yl)-5,7-dihydroxyc...
Source: ChemMedChem - October 6, 2023 Category: Chemistry Authors: Antonella Fais Francesca Pintus Benedetta Era Sonia Floris Amit Kumar Debapriyo Sarmadhikari Valeria Sogos Eugenio Uriarte Shailendra Asthana Maria Jo ão Matos Source Type: research