Article
Chemistry, Medicinal
Cheng Wang, Tian Hu, Jiayu Lu, Yuexin Lv, Shuai Ge, Yajing Hou, Huaizhen He
Summary: Allergic diseases are unfavorable immune responses caused by allergens, and the MRGPRX2 receptor on mast cells has been found to be associated with IgE-independent immune diseases and allergic reactions. Researchers have designed and synthesized a series of compounds called DPUs, which show promising anti-allergic effects in cell and animal experiments. The study also reveals the molecular mechanism of MRGPRX2 involvement in this process.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Hannah L. Stewart, Marta Bon, Corinne Wills, Mathew P. Martin, Lan Z. Wang, Eilidh S. Mackenzie, Paul G. Waddell, Michael J. Waring
Summary: Ureas are important in small molecule drugs and organic chemistry. Understanding their conformation is crucial for designing urea-containing bioactive compounds. In this study, we investigated N-aryl-N'‐cyclopentyl ureas with different N-methylation patterns and found that the methylation pattern significantly affects the conformational preference. Importantly, we discovered that N-phenyl-N'‐cyclopentyl urea can adopt both the trans-trans and cis-trans conformations with equal energy and that the presence of an internal hydrogen bond stabilizes the cis-trans conformation. These findings will be valuable for designing N-alkyl-N'‐aryl ureas as drug candidates.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Derek A. Leas, Austin G. Sanford, Jianbo Wu, Monica Cal, Marcel Kaiser, Sergio Wittlin, Ryan M. Hemsley, Elyssa B. Darner, LeeAnna M. Lui, Paul H. Davis, Jonathan L. Vennerstrom
Summary: This study assessed the physicochemical properties, in vitro ADME, and antiparasitic activity of eight N,N'-diarylureas as potential broad-spectrum antiprotozoal drugs. While all compounds had low intrinsic clearance values in human liver microsomes, their potency varied across different parasites, with one compound showing activity in mouse models of malaria and toxoplasmosis.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Kaifu Wu, Rui He, Zongyang Li, Kongxi Qiu, Guorong Xiao, Lijie Peng, Xiangbao Meng, Canhui Zheng, Zhang Zhang, Qian Cai
Summary: In this study, a new class of RET inhibitors, represented by compounds 17a/b, showed high selectivity to other kinases and exhibited potent inhibition against BaF3-CCDC6-RET cells with wild-type or gatekeeper mutation (V804M). Compound 17b demonstrated better pharmacokinetics properties and promising oral antitumor efficacy in an in vivo xenograft model, making it a potential lead compound for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
N. Babikova, A. Kobelev, A. Belozerova, M. Dmitriev, A. N. Maslivets
Summary: The reaction of 3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with symmetrical N,N'-disubstituted ureas yields 1,3-disubstituted 9-aroyl-8-hydroxy-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-triones, which have been confirmed by X-ray analysis. These resulting spiro heterocyclic systems containing a hydantoin fragment are of interest in the field of pharmaceutical chemistry.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Honglan Zeng, Hongyan Du, Xu Gong, Jie Zhang, Wei Han
Summary: A ligand-free palladium-catalyzed aerobic oxidative carbonylation of amines has been developed for the synthesis of ureas, including unsymmetrically N,N '-disubstituted ureas. This method offers a straightforward and efficient route to symmetrical and unsymmetrical ureas using inexpensive and readily available amines under mild conditions. By using oxygen as the sole oxidant, this novel method provides an attractive alternative to transition-metal-based oxidant systems.
Article
Chemistry, Organic
Yong Li, Jia Xu, Liu-Jun He, Ya-Fei Luo, Jiang-Ping Meng, Dian-Yong Tang, Hong-yu Li, Zhong-Zhu Chen, Zhi-Gang Xu
Summary: A novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts has been utilized to construct structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center. By varying the acid part in Ugi input, drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center can be rapidly generated using this method.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Karolis Skrickus, Jurate Siugzdaite, Raimundas Lelesius, Kazimieras Anusevicius, Birute Grybaite, Rita Vaickelioniene, Vytautas Mickevicius
Summary: A series of novel 1,2-bissubstituted disulfanes with various functional groups were synthesized and their antibacterial activities were evaluated. The MIC values for L. monocytogenes ranged from 3.9 to 62.5 μg/mL, and for S. aureus ranged from 7.8 to 250 μg/mL, with one exception of weaker MIC of 500 μg/mL. The MBC values for L. monocytogenes were found to be in the range of 7.8-250 μg/mL, while S. aureus demonstrated higher resistance with MBCs ranging from 7.8 to 500 μg/mL. The determined MBC/MIC ratios classified eleven compounds as bactericidal agents.
Article
Chemistry, Organic
Haijing Zhong, Tengbo Ding, Qifeng Guo, Zeng Tian, Pei Yu, Xiaojian Jiang
Summary: A catalytic asymmetric halocyclization protocol has been developed to synthesize morpholines containing a quaternary stereocenter. Various chlorinated 2,2-disubstituted morpholines were obtained in excellent yields and enantioselectivities under mild conditions using cinchona alkaloid-derived phthalazine as the catalyst.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Biochemistry & Molecular Biology
Elmira Gibadullina, Margarita Neganova, Yulia Aleksandrova, Hoang Bao Tran Nguyen, Alexandra Voloshina, Mikhail Khrizanforov, Thi Thu Nguyen, Ekaterina Vinyukova, Konstantin Volcho, Dmitry Tsypyshev, Anna Lyubina, Syumbelya Amerhanova, Anna Strelnik, Julia Voronina, Daut Islamov, Rakhmetulla Zhapparbergenov, Nurbol Appazov, Beauty Chabuka, Kimberley Christopher, Alexander Burilov, Nariman Salakhutdinov, Oleg Sinyashin, Igor Alabugin
Summary: This study explores the biological activity of a family of new hybrid molecules that combine sterically hindered phenols (SHPs) with additional urea/thiourea fragments. It finds that these compounds exhibit cytotoxic activity against tumor cells and have dual properties of pronounced antioxidant activity and increased reactive oxygen species generation. Molecular docking analysis reveals a potential target for these compounds. The most promising compounds can induce apoptosis in cancer cells through the intrinsic mitochondrial pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Anthony Choi, Ashraf El-Tunsi, Yuhang Wang, Anthony J. H. M. Meijer, Jia Li, Xiabing Li, Ilaria Proietti Silvestri, Iain Coldham
Summary: The kinetic resolution of 2-arylindolines was achieved by reacting N-tert-butoxycarbonyl (Boc) derivatives with n-butyllithium and sparteine, followed by electrophilic quenching. The study demonstrated that the rate of Boc rotation was fast and the enantioselectivity of the products could be controlled by the chiral ligand used. The enantioenriched products were successfully converted to 2,2-disubstituted compounds without significant loss in enantiopurity.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Sagarika Behera, Nabakumar Bera, Debayan Sarkar
Summary: The synthesis of 1,1-dialkyl-2,3-dihydro-indenols and 2,2-disubstituted chromans using an organo-acid catalyzed approach has been successfully achieved. The indane and chroman analogues offer valuable insights into the chemistry of biological systems. The reaction conditions and yields obtained in this study are superior to other available organo-catalytic strategies.
Article
Chemistry, Multidisciplinary
Fan Xu, Myles W. Smith
Summary: The newly developed method is versatile, easy to operate, and can be used for the synthesis of various complex alkaloids. The method can also be used to prepare spirocyclic indoxyl products.
Article
Chemistry, Medicinal
Ahmed E. Elsawi, Mostafa M. Elbadawi, Alessio Nocentini, Hadia Almahli, Simone Giovannuzzi, Moataz Shaldam, Rofaida Salem, Tamer M. Ibrahim, Hatem A. Abdel-Aziz, Claudiu T. Supuran, Wagdy M. Eldehna
Summary: Currently, dual targeting by a single small molecule is considered an effective strategy for cancer treatment. In this study, novel SLC-0111 analogues with dual inhibitory activities against CA IX/XII and VEGFR-2 were designed and synthesized. The inhibitory activities of these compounds were evaluated against a panel of hCAs, cancer cell lines, and breast cancer cell lines.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
V. V. Burmistrov, V. M. Mokhov, D. Danilov, R. R. Fayzullin, G. M. Butov
Summary: A high-yielding synthesis method for rac-1-[isocyanato(phenyl)methyl]adamantane was developed from a specific compound. A series of ureas and bis-ureas were synthesized through a series of reactions. Additionally, the structure of one of the starting compounds was confirmed by single crystal X-ray analysis.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Clotilde Philippe, Anh Thy Bui, Maxime Beau, Hugo Bloux, Francois Riobe, Olivier Mongin, Thierry Roisnel, Marie Cordier, Frederic Paul, Loic Lemiegre, Yann Trolez
Summary: In this study, 1,1,4,4-tetracyanobutadienes (TCBDs) carrying a wide variety of fluorophores were synthesized using a multi-step synthesis approach. The compounds were obtained from ynamides through a [2+2] cycloaddition/retroelectrocyclization reaction with tetracyanoethylene. The TCBDs exhibited remarkable emission properties across a wide range of wavelengths, from the visible region to the near-infrared (NIR) range. The quantum yields of these compounds in cyclohexane reached unexpectedly high values, up to 7.8%.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Pharmacology & Pharmacy
Tony Le Gall, Mathieu Berchel, Lee Davies, Angelique Mottais, Rosy Ghanem, Alain Fautrel, Deborah Gill, Steve Hyde, Pierre Lehn, Jean-Marie Lehn, Loic Lemiegre, Thierry Benvegnu, Paul-Alain Jaffres, Bruno Pitard, Tristan Montier
Summary: Aerosol lung gene therapy using non-viral delivery systems shows promise as a therapeutic strategy for chronic respiratory diseases. This study demonstrates that lipidic aminoglycoside derivative-based formulations possess efficient lung transfection activity following aerosol delivery, suggesting their potential as alternatives to GL67A.
Article
Chemistry, Organic
Clotilde Philippe, Maeva Coste, Yann Bretonniere, Loic Lemiegre, Sebastien Ulrich, Yann Trolez
Summary: This study reported a method for synthesizing TPE containing four ynamides, which was further converted into a tetra-TCBD derivative. Despite poor performance in solution, the tetra-TCBD compound exhibited near-infrared luminescence in the solid state, showing potential for future applications in molecular electronic devices.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
David P. Tilly, Jean-Paul Heeb, Simon J. Webb, Jonathan Clayden
Summary: Molecular biology controls complex reaction networks by translating a chemical input into an orthogonal chemical output, but dynamic foldamers have been limited by stereochenical changes that produce spectroscopic signals. In this study, the authors introduce an artificial molecular translation device that converts a chemical input into an unrelated chemical output. This device modulates the reactivity of an imidazole moiety by the presence of chloride ions through the allosteric remote control of imidazole tautomer states.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
David P. Tilly, David T. J. Morris, Jonathan Clayden
Summary: In this study, it was discovered that the ethylene-bridged hydrogen-bonded urea oligomer linear chain has reversible anion coordination and cascade conformational changes. The polarity reversals of hydrogen bonds in the oligomer propagate, resulting in a global switch of hydrogen-bond directionality. This induces a change in emission and excitation wavelengths of a fluorophore at the opposite terminus. Consequently, the molecule acts as a chemical sensor with a relayed remote spectroscopic response to varying anion concentrations. The anion-induced polarity switch provides an artificial communication mechanism for conveying information through oligomeric structures.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
David T. J. Morris, Steven M. Wales, Javier Echavarren, Matej Zabka, Giulia Marsico, John W. Ward, Natalie E. Pridmore, Jonathan Clayden
Summary: Cyclic triureas derived from TACN were synthesized and characterized. Dynamic cyclochirality was observed, with the hydrogen-bonded urea groups exchanging enantiomers through bowl inversion and directionality reversal. Structural modifications were found to affect the enantiomerization barrier, resulting in a planar-chiral, atropisomeric bowl-shaped structure with high stereochemical stability solely from its hydrogen-bonding network.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemical Research Methods
Jean-Paul Heeb, Jonathan Clayden, Martin D. Smith, Roly J. Armstrong
Summary: This article describes three experimental methods, namely kinetic analysis, dynamic HPLC, and variable-temperature NMR, for measuring the rate of racemization in atropisomers. Atropisomers are molecules that exhibit stereochemistry from restricted bond rotation and are highly relevant in catalysis, medicine, and materials science. The methods presented in this article provide techniques for evaluating the configurational stability of atropisomeric molecules and can be performed using standard analytical equipment. The article also discusses the selection of a suitable method for determining racemization rates for new molecular structures with unknown properties.
Editorial Material
Pharmacology & Pharmacy
Danette L. Daniels, Gopal P. Sapkota, Lyn H. Jones
Summary: Targeted protein degradation (TPD) is a promising therapy development strategy, with newer TPD technologies being developed for the treatment of cancer and various diseases. Jerry Madukwe, the editor-in-chief of Trends in Pharmacological Sciences (TIPS), asked experts in the field to reflect on the global challenges and future of TPD.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Editorial Material
Pharmacology & Pharmacy
Breanna L. Zerfas, Lyn H. Jones
Summary: In this study, Sun et al. developed R-spondin chimeras (ROTACs) that can effectively degrade PD-L1 and potentially be applied to other membrane proteins, offering a potential therapeutic option for expanding the druggable proteome.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Chemistry, Medicinal
Justin T. Cruite, Radoslaw P. Nowak, Katherine A. Donovan, Scott B. Ficarro, Huang Huang, Hu Liu, Yingpeng Liu, Jarrod A. Marto, Rebecca J. Metivier, Eric S. Fischer, Lyn H. Jones
Summary: Site-specific modification of amino acid residues in protein binding pockets using sulfonyl exchange chemistry expands the druggable proteome. The development of sulfonyl imidazole and related sulfur(VI)-diazole exchange (SuDEx) warheads enhances stability leading to efficient labeling of His353, highlighting its potential for covalent drug development and therapeutic targeting of specific histidine residues.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Ellie Stammers, Chris D. Parsons, Jonathan Clayden, Alastair J. J. Lennox
Summary: In this paper, an electrochemical method is described for the synthesis of biaryls through metal-catalyst-free coupling. The temporary formation and reduction of ureas are utilized to enhance the synthesis yield.
NATURE COMMUNICATIONS
(2023)
Review
Chemistry, Multidisciplinary
David T. J. Morris, Jonathan Clayden
Summary: Biological systems and foldamer chemistry both exploit the propagation of conformational change to communicate information on the molecular scale. Switchable screw-sense preference is a communication mechanism that utilizes dynamic helical foldamers to transmit information. This review discusses the functional requirements for communication devices and describes the use of various stimuli to switch the screw sense. It also explores how conformational switching can control chemical events remote from the source of information.
CHEMICAL SOCIETY REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Radoslaw P. Nowak, Jianwei Che, Silas Ferrao, Nikki R. Kong, Hu Liu, Breanna L. Zerfas, Lyn H. Jones
Summary: Thalidomide and its derivatives are molecular glues that bind cereblon (CRBN), a component of an E3 ubiquitin ligase complex, and mediate protein interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. The structural features of neosubstrate binding have been elucidated that highlight key interactions with a beta-hairpin degron containing a glycine, which is present in a wide-range of proteins, including zinc-finger transcription factors such as IKZF1, and the translation termination factor GSPT1. Here, we profile 14 closely-related thalidomide derivatives in CRBN occupancy, and IKZF1 and GSPT1 degradation cell-based assays, and use crystal structures, computational docking and molecular dynamics to delineate subtle structure-activity relationships. Our findings will enable the rational design of CRBN modulators in the future, and help avoid the degradation of GSPT1 which is broadly cytotoxic.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Radoslaw P. Nowak, Leah Ragosta, Fidel Huerta, Hu Liu, Scott B. Ficarro, Justin T. Cruite, Rebecca J. Metivier, Katherine A. Donovan, Jarrod A. Marto, Eric S. Fischer, Breanna L. Zerfas, Lyn H. Jones
Summary: This study developed efficient PROTAC degraders using covalent CRBN ligands, which showed enhanced pharmacodynamics and expanded the scope of targets for heterobifunctional degraders.
RSC CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
David P. Tilly, Matej Zabka, Inigo Vitorica-Yrezabal, Hazel A. Sparkes, Natalie Pridmore, Jonathan Clayden
Summary: This paper investigates the formation mechanism of higher-order structures of ethylene-bridged oligoureas in both crystalline and solution states. The oligoureas self-assemble into supramolecular nanorings or helical chains through hydrogen bonding interactions. The formation of intermolecular hydrogen bonds at the terminus of the oligoureas switches the directionality of the hydrogen bond chain, promoting further assembly. The helices in the crystal state have identical handedness and polarity, and the interactions in solution are consistent with those in the crystals. The switch of hydrogen bond polarity propagates intermolecularly, constituting an example of intermolecular communication within supramolecular polymers.
Article
Chemistry, Organic
Faiza Diaba, Gisela Trenchs
Summary: The first violet light-mediated synthesis of gamma- and delta-lactams from N-alkenyl trichloroacetamides is reported in this paper. The reactions are conducted in tetrahydrofuran or 2-methyltetrahydrofuran as the sole solvent without catalysts or additives, under non-anhydrous conditions in an air atmosphere where the solvent serves as the radical initiator.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Feroze Hussain, Sajjad Ahmed, Ashiq Hussain Padder, Qazi Naveed Ahmed
Summary: This study reports a novel and efficient one-pot synthesis method for mixed phosphorotrithioates, which does not require supplementary additives and shows broad applicability.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Hyunjin Oh, Ikyon Kim
Summary: A new 1,2,4-triazole-pyrrolo[1,2-a]pyrazine hybrid system, 6-acylpyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine, was synthesized using a catalyst-free method. This method involved sequential exposure of pyrrole-2-carbonitrile-derived substrates to DMF-DMA and acyl hydrazide, resulting in the formation of acylated pyrazine and 1,2,4-triazole rings, enabling the installation of various substituents at specific positions on the core skeleton.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Ming Yan, Si-fan Wang, Yong-po Zhang, Jin-zhong Zhao, Zhuo Tang, Guang-xun Li
Summary: Here we developed an efficient photocatalytic approach for the convenient preparation of sulfinamides. The reaction allows for the gram-scale preparation of sulfinamides and the one-pot synthesis of various sulfonyl amides.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Farzaneh Bandehali-Naeini, Zahra Tanbakouchian, Noushin Farajinia-Lehi, Nicolas Mayer, Morteza Shiri, Martin Breugst
Summary: Two tandem catalytic systems were developed for the synthesis of novel 3,4-disubstituted maleimides using the same Ugi adducts. Different maleimide structures can be synthesized using either Pd or Cu catalysis.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Tanya Raghava, Anjan Chattopadhyay, Subhadeep Banerjee, Nivedita Sarkar
Summary: Amine substitution of two ortho fluorine atoms of tetrafluoroterephthalonitrile through SNAr chemistry is easily achievable. But further fluorine substitution is only possible under forcing conditions, yielding valuable fluorophores for bioimaging.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Review
Chemistry, Organic
Anju Chadha, Santosh Kumar Padhi, Selvaraj Stella, Sowmyalakshmi Venkataraman, Thangavelu Saravanan
Summary: Alcohol dehydrogenases are enzymes that use cofactors for oxidation or reduction reactions of alcohols or carbonyl compounds. They are utilized in green chemistry and have applications in the production of pharmaceuticals. Recombinant enzymes have solved the challenge of producing purified enzymes in large quantities. Engineered alcohol dehydrogenases have been used in asymmetric synthesis in industry. Various methods have been established for regenerating expensive cofactors to make the enzymatic process more efficient and economically viable.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
