Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones
ChemMedChem. 2023 Dec 21:e202300519. doi: 10.1002/cmdc.202300519. Online ahead of print.ABSTRACTSynthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds wi...
Source: ChemMedChem - December 21, 2023 Category: Chemistry Authors: Agata Jaskulska Jacek Szyma ński Piotr F J Lipi ński Jakub Modranka Anna E Janecka Tomasz Janecki Katarzyna Gach-Janczak Source Type: research
Design, Synthesis and Biological Evaluation of Novel Anticancer Amidinourea Analogues via Unexpected 1,3,5-Triazin-2-one Ring Opening
ChemMedChem. 2023 Dec 21:e202300493. doi: 10.1002/cmdc.202300493. Online ahead of print.ABSTRACTAmidinoureas are an understudied class of molecules with unique structural properties and biological activities. A simple methodology has been developed for the synthesis of aliphatic substituted amidinoureas via unexpected cycle opening of benzothiazolo-1,3,5-triazine-2-ones and transamination reaction of N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)aniline-1-carboxamide in good yields. A novel series of amidinoureas derivatives was designed, synthesized, and evaluated for its antiproliferative activity on an aggressive metastatic ...
Source: ChemMedChem - December 21, 2023 Category: Chemistry Authors: Oleksandr Grytsai Nedra Hamouda-Tekaya Thomas Botton Stephane Rocchi Rachid Benhida Cyril Ronco Source Type: research
Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones
ChemMedChem. 2023 Dec 21:e202300519. doi: 10.1002/cmdc.202300519. Online ahead of print.ABSTRACTSynthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds wi...
Source: ChemMedChem - December 21, 2023 Category: Chemistry Authors: Agata Jaskulska Jacek Szyma ński Piotr F J Lipi ński Jakub Modranka Anna E Janecka Tomasz Janecki Katarzyna Gach-Janczak Source Type: research
Design, Synthesis and Biological Evaluation of Novel Anticancer Amidinourea Analogues via Unexpected 1,3,5-Triazin-2-one Ring Opening
ChemMedChem. 2023 Dec 21:e202300493. doi: 10.1002/cmdc.202300493. Online ahead of print.ABSTRACTAmidinoureas are an understudied class of molecules with unique structural properties and biological activities. A simple methodology has been developed for the synthesis of aliphatic substituted amidinoureas via unexpected cycle opening of benzothiazolo-1,3,5-triazine-2-ones and transamination reaction of N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)aniline-1-carboxamide in good yields. A novel series of amidinoureas derivatives was designed, synthesized, and evaluated for its antiproliferative activity on an aggressive metastatic ...
Source: ChemMedChem - December 21, 2023 Category: Chemistry Authors: Oleksandr Grytsai Nedra Hamouda-Tekaya Thomas Botton Stephane Rocchi Rachid Benhida Cyril Ronco Source Type: research
Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones
ChemMedChem. 2023 Dec 21:e202300519. doi: 10.1002/cmdc.202300519. Online ahead of print.ABSTRACTSynthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds wi...
Source: ChemMedChem - December 21, 2023 Category: Chemistry Authors: Agata Jaskulska Jacek Szyma ński Piotr F J Lipi ński Jakub Modranka Anna E Janecka Tomasz Janecki Katarzyna Gach-Janczak Source Type: research
Structure-Based Design of AG-946, a Pyruvate Kinase Activator
We describe the structure-based design of compound 27 (AG-946), an activator of PK isoforms, including red blood cell (RBC)-specific isoforms of PK (PKR), designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency towards PKR while reducing activity against off-targets observed from the original scaffold. Compound 27 (AG-946) demonstrated (1) activation of human wild-type PK (half maximal activation concentration [AC50]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50=0.0043 μM] and R510Q [AC50=0.0069 μM]), (2) displayed a significantly longer half-t...
Source: ChemMedChem - December 18, 2023 Category: Chemistry Authors: Tao Liu Anil K Padyana Evan T Judd Lei Jin Dalia Hammoudeh Charles Kung Lenny Dang Source Type: research
Structure-Based Design of AG-946, a Pyruvate Kinase Activator
We describe the structure-based design of compound 27 (AG-946), an activator of PK isoforms, including red blood cell (RBC)-specific isoforms of PK (PKR), designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency towards PKR while reducing activity against off-targets observed from the original scaffold. Compound 27 (AG-946) demonstrated (1) activation of human wild-type PK (half maximal activation concentration [AC50]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50=0.0043 μM] and R510Q [AC50=0.0069 μM]), (2) displayed a significantly longer half-t...
Source: ChemMedChem - December 18, 2023 Category: Chemistry Authors: Tao Liu Anil K Padyana Evan T Judd Lei Jin Dalia Hammoudeh Charles Kung Lenny Dang Source Type: research
Structure-Based Design of AG-946, a Pyruvate Kinase Activator
We describe the structure-based design of compound 27 (AG-946), an activator of PK isoforms, including red blood cell (RBC)-specific isoforms of PK (PKR), designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency towards PKR while reducing activity against off-targets observed from the original scaffold. Compound 27 (AG-946) demonstrated (1) activation of human wild-type PK (half maximal activation concentration [AC50]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50=0.0043 μM] and R510Q [AC50=0.0069 μM]), (2) displayed a significantly longer half-t...
Source: ChemMedChem - December 18, 2023 Category: Chemistry Authors: Tao Liu Anil K Padyana Evan T Judd Lei Jin Dalia Hammoudeh Charles Kung Lenny Dang Source Type: research
Cyclic diacyl thioureas enhance activity of corrector Lumacaftor on F508del-CFTR
ChemMedChem. 2023 Dec 17:e202300391. doi: 10.1002/cmdc.202300391. Online ahead of print.ABSTRACTCystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del-CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6i displayed the most marked enhancing effect...
Source: ChemMedChem - December 17, 2023 Category: Chemistry Authors: Andrea Spallarossa Nicoletta Pedemonte Emanuela Pesce Enrico Millo Elena Cichero Camillo Rosano Matteo Lusardi Erika Iervasi Marco Ponassi Source Type: research
Cyclic diacyl thioureas enhance activity of corrector Lumacaftor on F508del-CFTR
ChemMedChem. 2023 Dec 17:e202300391. doi: 10.1002/cmdc.202300391. Online ahead of print.ABSTRACTCystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del-CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6i displayed the most marked enhancing effect...
Source: ChemMedChem - December 17, 2023 Category: Chemistry Authors: Andrea Spallarossa Nicoletta Pedemonte Emanuela Pesce Enrico Millo Elena Cichero Camillo Rosano Matteo Lusardi Erika Iervasi Marco Ponassi Source Type: research
Straightforward Synthesis of DFO* - An Octadentate Chelator for Zirconium-89
ChemMedChem. 2023 Dec 16:e202300495. doi: 10.1002/cmdc.202300495. Online ahead of print.ABSTRACTDFO* is an octadentate chelator able to form highly stable chelates with Zirconium-89 (89Zr) for nuclear medicinal applications in Positron Emission Tomography (PET) [1,2]. The synthesis of DFO* and its scale-up remains challenging by reported synthetic protocols. For this reason, we set out to develop a de novo synthesis of a hydroxamate-containing building block suitable for the coupling to the commercially available DFO (desferrioxamine B, mesylate salt) yielding, after deprotection, the desired chelator DFO* in a more effici...
Source: ChemMedChem - December 16, 2023 Category: Chemistry Authors: Xabier Guarrochena Julia Kronberger Manuel Tieber Philipp Ciesielski Thomas L Mindt Irene V J Feiner Source Type: research
Naturally Occurring and Widespread Resistance to Bioactive Natural Products
ChemMedChem. 2023 Dec 16:e202300619. doi: 10.1002/cmdc.202300619. Online ahead of print.ABSTRACTNaturally occurring resistances diminish the effectiveness of antibiotics, and present significant challenges to human health. Human activities are usually considered as the main drivers of the dissemination of antibiotic resistance, however, the origin of the clinical antibiotic resistance can be traced to the environmental microbes, and the clinically relevant resistance determinants have already pre-existed in nature before the antibiotics come into clinic. In this concept, we present the naturally occurring and widespread re...
Source: ChemMedChem - December 16, 2023 Category: Chemistry Authors: Bin Tan Qingbo Zhang Liping Zhang Yiguang Zhu Changsheng Zhang Source Type: research
Straightforward Synthesis of DFO* - An Octadentate Chelator for Zirconium-89
ChemMedChem. 2023 Dec 16:e202300495. doi: 10.1002/cmdc.202300495. Online ahead of print.ABSTRACTDFO* is an octadentate chelator able to form highly stable chelates with Zirconium-89 (89Zr) for nuclear medicinal applications in Positron Emission Tomography (PET) [1,2]. The synthesis of DFO* and its scale-up remains challenging by reported synthetic protocols. For this reason, we set out to develop a de novo synthesis of a hydroxamate-containing building block suitable for the coupling to the commercially available DFO (desferrioxamine B, mesylate salt) yielding, after deprotection, the desired chelator DFO* in a more effici...
Source: ChemMedChem - December 16, 2023 Category: Chemistry Authors: Xabier Guarrochena Julia Kronberger Manuel Tieber Philipp Ciesielski Thomas L Mindt Irene V J Feiner Source Type: research
Naturally Occurring and Widespread Resistance to Bioactive Natural Products
ChemMedChem. 2023 Dec 16:e202300619. doi: 10.1002/cmdc.202300619. Online ahead of print.ABSTRACTNaturally occurring resistances diminish the effectiveness of antibiotics, and present significant challenges to human health. Human activities are usually considered as the main drivers of the dissemination of antibiotic resistance, however, the origin of the clinical antibiotic resistance can be traced to the environmental microbes, and the clinically relevant resistance determinants have already pre-existed in nature before the antibiotics come into clinic. In this concept, we present the naturally occurring and widespread re...
Source: ChemMedChem - December 16, 2023 Category: Chemistry Authors: Bin Tan Qingbo Zhang Liping Zhang Yiguang Zhu Changsheng Zhang Source Type: research
Synthesis and Antiproliferative Evaluation of d-Glucuronamide-Based Nucleosides and (Triazolyl)methyl Amide-Linked Pseudodisaccharide Nucleosides
ChemMedChem. 2023 Dec 14:e202300608. doi: 10.1002/cmdc.202300608. Online ahead of print.ABSTRACTThe synthesis and antiproliferative evaluation of novel d-glucopyranuronamide-containing nucleosides is described. Based on our previously reported anticancer d-glucuronamide-based nucleosides, new analogues comprising N/O-dodecyl or N-propargyl substituents at the glucuronamide unit and anomerically-N-linked 2-acetamido-6-chloropurine, 6-chloropurine or 4-(6-chloropurinyl)methyl triazole motifs were synthesized in 4-6 steps starting from acetonide-protected glucofuranurono-6,3-lactone. The methodologies were based on the access...
Source: ChemMedChem - December 14, 2023 Category: Chemistry Authors: T ânia Moreira Domingos M Manuel Joana Rosa Rafael Santana Nunes Veronika Voj áčková Radek Jorda M Concei ção Oliveira Nuno M Xavier Source Type: research
