Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors
ChemMedChem. 2024 Feb 22:e202400057. doi: 10.1002/cmdc.202400057. Online ahead of print.ABSTRACTA 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar to that observed for the P1 group of benzamidine-derived peptidic furin inhibitors suggesting an aminomethyl substitution of this fragment to obtain a couplable P1 residue for the synthesis of substrate-analogue furin inhibitors. The obtained inhibitors possess a slightly improved...
Source: ChemMedChem - February 22, 2024 Category: Chemistry Authors: Roman W Lange Konstantin Bloch Miriam Ruth Heindl Jan Wollenhaupt Manfred S Weiss Hans Brandstetter Gerhard Klebe Franco H Falcone Eva B öttcher-Friebertshäuser Sven O Dahms Torsten Steinmetzer Source Type: research
Identification of ß-Glucocerebrosidase Activators for Glucosylceramide hydrolysis
ChemMedChem. 2024 Feb 21:e202300548. doi: 10.1002/cmdc.202300548. Online ahead of print.ABSTRACTSeveral novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have distinct chemotypes. Positive allosteric modulators bind to a site on GCase and induce conformational changes, but also induce an equilibrium state between monomer and dimer.PMID:38381042 | DOI:10.1002/cmdc.202300548 (Source: ChemMedChem)
Source: ChemMedChem - February 21, 2024 Category: Chemistry Authors: Monika-Sarah E D Schulze Diana Scholz Eric Jnoff Adrian Hall Jonathan Melin Zara A Sands Elizabeth Rodriguez Veronique M Andre Source Type: research
Identification of ß-Glucocerebrosidase Activators for Glucosylceramide hydrolysis
ChemMedChem. 2024 Feb 21:e202300548. doi: 10.1002/cmdc.202300548. Online ahead of print.ABSTRACTSeveral novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have distinct chemotypes. Positive allosteric modulators bind to a site on GCase and induce conformational changes, but also induce an equilibrium state between monomer and dimer.PMID:38381042 | DOI:10.1002/cmdc.202300548 (Source: ChemMedChem)
Source: ChemMedChem - February 21, 2024 Category: Chemistry Authors: Monika-Sarah E D Schulze Diana Scholz Eric Jnoff Adrian Hall Jonathan Melin Zara A Sands Elizabeth Rodriguez Veronique M Andre Source Type: research
Accelerating BRPF1b hit identification with BioPhysical and Active Learning Screening (BioPALS)
We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET parameters. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics are determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to wide range of biologic...
Source: ChemMedChem - February 19, 2024 Category: Chemistry Authors: Sandeep Pal Zandile Nare Vincenzo A Rao Brian O Smith Ian Morrison Edward A Fitzgerald Andrew Scott Matilda Jane Bingham Thomas Pesnot Source Type: research
Accelerating BRPF1b hit identification with BioPhysical and Active Learning Screening (BioPALS)
We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET parameters. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics are determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to wide range of biologic...
Source: ChemMedChem - February 19, 2024 Category: Chemistry Authors: Sandeep Pal Zandile Nare Vincenzo A Rao Brian O Smith Ian Morrison Edward A Fitzgerald Andrew Scott Matilda Jane Bingham Thomas Pesnot Source Type: research
Investigating the Combined Toxicity of Cu(II) and Carbon Monoxide (CO); Cellular CO Delivery using a Cu(II) Flavonolato Complex
ChemMedChem. 2024 Feb 18:e202300682. doi: 10.1002/cmdc.202300682. Online ahead of print.ABSTRACTCarbon monoxide (CO) delivery molecules are of significant current interest as potential therapeutics, including for anticancer applications. A recent approach toward generating new types of materials-based anticancer agents involves combining the Fenton reactivity of a redox active metal ion with CO delivery. However, small molecule examples of these types entities have not been systematically studied to evaluate the combined effect on cellular toxicity. Herein we describe a Cu(II) flavonolato complex which produces anticancer ...
Source: ChemMedChem - February 18, 2024 Category: Chemistry Authors: Stephen N Anderson C Taylor Dederich Josiah G D Elsberg Abby D Benninghoff Lisa M Berreau Source Type: research
Nano-Engineering Strategies for Tumor-Specific Therapy
ChemMedChem. 2024 Feb 14:e202300647. doi: 10.1002/cmdc.202300647. Online ahead of print.ABSTRACTNanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor-specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitiv...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Zijin Li Hai-Yan Xie Weidong Nie Source Type: research
Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors
ChemMedChem. 2024 Feb 15:e202400004. doi: 10.1002/cmdc.202400004. Online ahead of print.ABSTRACTA new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benznesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for invitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, diffe...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Ehab S Taher Adel A Marzouk Walaa Hamada Abd-Allah Simone Giovannuzzi Tarek S Ibrahim Claudiu T Supuran Mohamed A El Hamd Mohammed Farrag Mohammed Ali El-Behairy Source Type: research
Helical BODIPY Dyes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer
ChemMedChem. 2024 Feb 15:e202400041. doi: 10.1002/cmdc.202400041. Online ahead of print.ABSTRACTDespite of having many advantages over the popular cancer therapies, photodynamic therapy still is not widely acceptable for clinical applications. Scarcity of efficient triplet photosensitizers (PSs) is one of the main bottlenecks for this. Although numerous heavy atom attached PSs are developed, but these are not suitable for clinical applications. Thus, development of heavy-atom-free organic PSs is urgently required. Here, development of new type of helical BODIPYs as PSs for PDT is discussed. BODIPYs have rich photophysical ...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Soumyaditya Mula Mrunesh Koli Source Type: research
Nano-Engineering Strategies for Tumor-Specific Therapy
ChemMedChem. 2024 Feb 14:e202300647. doi: 10.1002/cmdc.202300647. Online ahead of print.ABSTRACTNanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor-specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitiv...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Zijin Li Hai-Yan Xie Weidong Nie Source Type: research
Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors
ChemMedChem. 2024 Feb 15:e202400004. doi: 10.1002/cmdc.202400004. Online ahead of print.ABSTRACTA new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benznesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for invitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, diffe...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Ehab S Taher Adel A Marzouk Walaa Hamada Abd-Allah Simone Giovannuzzi Tarek S Ibrahim Claudiu T Supuran Mohamed A El Hamd Mohammed Farrag Mohammed Ali El-Behairy Source Type: research
Helical BODIPY Dyes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer
ChemMedChem. 2024 Feb 15:e202400041. doi: 10.1002/cmdc.202400041. Online ahead of print.ABSTRACTDespite of having many advantages over the popular cancer therapies, photodynamic therapy still is not widely acceptable for clinical applications. Scarcity of efficient triplet photosensitizers (PSs) is one of the main bottlenecks for this. Although numerous heavy atom attached PSs are developed, but these are not suitable for clinical applications. Thus, development of heavy-atom-free organic PSs is urgently required. Here, development of new type of helical BODIPYs as PSs for PDT is discussed. BODIPYs have rich photophysical ...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Soumyaditya Mula Mrunesh Koli Source Type: research
Nano-Engineering Strategies for Tumor-Specific Therapy
ChemMedChem. 2024 Feb 14:e202300647. doi: 10.1002/cmdc.202300647. Online ahead of print.ABSTRACTNanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor-specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitiv...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Zijin Li Hai-Yan Xie Weidong Nie Source Type: research
Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors
ChemMedChem. 2024 Feb 15:e202400004. doi: 10.1002/cmdc.202400004. Online ahead of print.ABSTRACTA new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benznesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for invitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, diffe...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Ehab S Taher Adel A Marzouk Walaa Hamada Abd-Allah Simone Giovannuzzi Tarek S Ibrahim Claudiu T Supuran Mohamed A El Hamd Mohammed Farrag Mohammed Ali El-Behairy Source Type: research
Helical BODIPY Dyes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer
ChemMedChem. 2024 Feb 15:e202400041. doi: 10.1002/cmdc.202400041. Online ahead of print.ABSTRACTDespite of having many advantages over the popular cancer therapies, photodynamic therapy still is not widely acceptable for clinical applications. Scarcity of efficient triplet photosensitizers (PSs) is one of the main bottlenecks for this. Although numerous heavy atom attached PSs are developed, but these are not suitable for clinical applications. Thus, development of heavy-atom-free organic PSs is urgently required. Here, development of new type of helical BODIPYs as PSs for PDT is discussed. BODIPYs have rich photophysical ...
Source: ChemMedChem - February 15, 2024 Category: Chemistry Authors: Soumyaditya Mula Mrunesh Koli Source Type: research
