Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 160.563
Filtrar
1.
Curr Protoc ; 4(2): e984, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38327099

RESUMO

A simple, reliable, and efficient method for the gram-scale chemical synthesis of pyrimidine nucleosides functionalized with C5-carboxyl, nitrile, ester, amide, or amidine, starting from unprotected uridine and cytidine, is described. The protocol involves the synthesis of 5-trifluoromethyluridine and 5-trifluoromethylcytidine with Langlois reagent (CF3 SO2 Na) in the presence of tert-butyl hydroperoxide and subsequent transformation of the CF3 group to the C5-C 'carbon substituents' under alkaline conditions. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Synthesis and characterization of 5-trifluoromethyluridine (5-CF3 U) and 5-trifluoromethylcytidine (5-CF3 C) Basic Protocol 2: Conversion of 5-CF3 U and 5-CF3 C to several C5-substituted ribonucleosides.


Assuntos
Química Orgânica , Nucleosídeos de Pirimidina , Citidina/análogos & derivados , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Ribonucleosídeos/química , Uridina/análogos & derivados , Química Orgânica/métodos
2.
Curr Protoc ; 4(2): e983, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38327123

RESUMO

This protocol describes a method for the incorporation of sensitive functional groups into oligodeoxynucleotides (ODNs). The nucleophile-sensitive epigenetic N4-acetyldeoxycytosine (4acC) DNA modification is used as an example, but other sensitive groups can also be incorporated, e.g., alkyl halide, α-haloamide, alkyl ester, aryl ester, thioester, and chloropurine groups, all of which are unstable under the basic and nucleophilic deprotection and cleavage conditions used in standard ODN synthesis methods. The method uses a 1,3-dithian-2-yl-methoxycarbonyl (Dmoc) group that carries a methyl group at the carbon of the methoxy moiety (meDmoc) for the protection of exo-amines of nucleobases. The growing ODN is anchored to a solid support via a Dmoc linker. With these protecting and linking strategies, ODN deprotection and cleavage are achieved without using any strong bases and nucleophiles. Instead, they can be carried out under nearly neutral non-nucleophilic oxidative conditions. To increase the length of ODNs that can be synthesized using the meDmoc method, the protocol also describes the synthesis of a PEGylated Dmoc (pDmoc) phosphoramidite. With some of the nucleotides being incorporated with pDmoc-CE phosphoramidite, the growing ODN on the solid support carries PEG moieties and becomes more soluble, thus enabling longer ODN synthesis. The ODN synthesis method described in this protocol is expected to make many sensitive ODNs that are difficult to synthesize accessible to researchers in multiple areas, such as epigenetics, nanopore sequencing, nucleic acid-protein interactions, antisense drug development, DNA alkylation carcinogenesis, and DNA nanotechnology. © 2024 Wiley Periodicals LLC. Basic Protocol: Sensitive ODN synthesis Support Protocol 1: Synthesis of meDmoc-CE phosphoramidites Support Protocol 2: Synthesis of a pDmoc-CE phosphoramidite.


Assuntos
Oligodesoxirribonucleotídeos , Compostos Organofosforados , DNA , Ésteres , Oligodesoxirribonucleotídeos/síntese química
3.
Science ; 383(6684): 721-726, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38359125

RESUMO

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.


Assuntos
Antibacterianos , Hidrocarbonetos Aromáticos com Pontes , Farmacorresistência Bacteriana Múltipla , Lincosamidas , Oxepinas , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Eritromicina/química , Eritromicina/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Oxepinas/síntese química , Oxepinas/química , Oxepinas/farmacologia , Lincosamidas/síntese química , Lincosamidas/química , Lincosamidas/farmacologia , Animais , Camundongos , Desenho de Fármacos , Ribossomos/química
4.
Science ; 383(6685): 911-918, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38386754

RESUMO

Coenzyme A (CoA) is essential to all life on Earth, and its functional subunit, pantetheine, is important in many origin-of-life scenarios, but how pantetheine emerged on the early Earth remains a mystery. Earlier attempts to selectively synthesize pantetheine failed, leading to suggestions that "simpler" thiols must have preceded pantetheine at the origin of life. In this work, we report high-yielding and selective prebiotic syntheses of pantetheine in water. Chemoselective multicomponent aldol, iminolactone, and aminonitrile reactions delivered spontaneous differentiation of pantoic acid and proteinogenic amino acid syntheses, as well as the dihydroxyl, gem-dimethyl, and ß-alanine-amide moieties of pantetheine in dilute water. Our results are consistent with a role for canonical pantetheine at the outset of life on Earth.


Assuntos
Coenzima A , Origem da Vida , Panteteína , Coenzima A/química , Panteteína/síntese química , Água/química , Nitrilas/química , Hidroxibutiratos/síntese química , 4-Butirolactona/síntese química , Aminoácidos/síntese química
5.
Science ; 383(6685): 849-854, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38386756

RESUMO

Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines.


Assuntos
Alcaloides , Briozoários , Alcaloides/síntese química , Alcenos/química , Azidas/química , Elétrons , Animais , Catálise , Oxirredução
6.
Nature ; 626(7997): 45-57, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38297170

RESUMO

The linear production and consumption of plastics today is unsustainable. It creates large amounts of unnecessary and mismanaged waste, pollution and carbon dioxide emissions, undermining global climate targets and the Sustainable Development Goals. This Perspective provides an integrated technological, economic and legal view on how to deliver a circular carbon and plastics economy that minimizes carbon dioxide emissions. Different pathways that maximize recirculation of carbon (dioxide) between plastics waste and feedstocks are outlined, including mechanical, chemical and biological recycling, and those involving the use of biomass and carbon dioxide. Four future scenarios are described, only one of which achieves sufficient greenhouse gas savings in line with global climate targets. Such a bold system change requires 50% reduction in future plastic demand, complete phase-out of fossil-derived plastics, 95% recycling rates of retrievable plastics and use of renewable energy. It is hard to overstate the challenge of achieving this goal. We therefore present a roadmap outlining the scale and timing of the economic and legal interventions that could possibly support this. Assessing the service lifespan and recoverability of plastic products, along with considerations of sufficiency and smart design, can moreover provide design principles to guide future manufacturing, use and disposal of plastics.


Assuntos
Poluição Ambiental , Objetivos , Plásticos , Reciclagem , Desenvolvimento Sustentável , Biomassa , Dióxido de Carbono/análise , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Poluição Ambiental/economia , Poluição Ambiental/legislação & jurisprudência , Poluição Ambiental/prevenção & controle , Poluição Ambiental/estatística & dados numéricos , Combustíveis Fósseis , Aquecimento Global/prevenção & controle , Gases de Efeito Estufa/análise , Plásticos/síntese química , Plásticos/economia , Plásticos/metabolismo , Plásticos/provisão & distribuição , Reciclagem/economia , Reciclagem/legislação & jurisprudência , Reciclagem/métodos , Reciclagem/tendências , Energia Renovável , Desenvolvimento Sustentável/economia , Desenvolvimento Sustentável/legislação & jurisprudência , Desenvolvimento Sustentável/tendências , Tecnologia/economia , Tecnologia/legislação & jurisprudência , Tecnologia/métodos , Tecnologia/tendências
7.
Org Lett ; 26(5): 1094-1099, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38277138

RESUMO

Utilizing already existing DNA-encoded libraries (DELs) for the generation of a distinct DEL represents an expedited strategy for expanding the chemical space. Herein, we leverage the unique photoreactivity of tetrazoles to synthesize diacylhydrazines on DNA. Widely available carboxylic acids serving as building blocks were employed under the mild photomediated reaction conditions, affording diverse DNA-conjugated diacylhydrazines. This methodology also demonstrates robustness in DEL-compatible synthesis and facilitates the preparation of oligonucleotide-based chemical probes.


Assuntos
DNA , Biblioteca Gênica , Ácidos Carboxílicos , Bibliotecas de Moléculas Pequenas/síntese química
8.
Org Lett ; 26(5): 1073-1077, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38277646

RESUMO

Asymmetric de novo construction of limonoids remains a challenging problem in stereoselective synthesis due to the diverse and complex structures associated with this class of natural products. Here, a unique synthetic pathway to an "intact" limonoid system is described. The synthetic route is based on exploiting an oxidative rearrangement reaction of a densely functionalized late-stage intermediate to simultaneously establish the stereodefined C10 quaternary center and an allylic acetate at C12. This is a unique example of a complex rearrangement reaction that proceeds on a system whose presumed intermediate allyl cation is highly hindered and lacks neighboring protons that are otherwise required for cation termination.


Assuntos
Limoninas , Cátions , Limoninas/síntese química , Estereoisomerismo
9.
Bioorg Chem ; 144: 107105, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38219482

RESUMO

As regards to the structural analysis and optimization of diverse potential EGFR inhibitors, two series of imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates were designed and constructed as potential EGFR suppressors. The cytotoxic effect of the prepared derivatives was assessed toward hepatic, breast, and prostate cancerous cells (Hep-G2, MCF-7, and PC-3). Three derivatives 3d, 3e, and 3f presented potent antiproliferative activity and selectivity against the examined tumor cells showing IC50 values at low micromolar levels. Hence, successive biological assays were applied to determine the probable mechanism of action of the new compounds. They exhibited significant EGFR suppression with an IC50 range of 0.137-0.507 µM. The most effective EGFR inhibitor 3f arrested the MCF-7 cell cycle at the S phase by inducing the apoptotic pathway that was confirmed via increasing the expression of Caspases 8, 9, and Bax, which are associated with Bcl-2 decline. Additionally, molecular docking displayed a distinctive interaction between 3f and EGFR binding pocket. Overall, this work introduces some novel imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates as potential cytotoxic and EGFR inhibitors that deserve further research in tumor therapy.


Assuntos
Antineoplásicos , Apoptose , Imidazóis , Humanos , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases , Relação Estrutura-Atividade , Isotiurônio/análogos & derivados , Isotiurônio/síntese química , Isotiurônio/química
10.
Science ; 382(6671): eabo7201, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37943932

RESUMO

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.


Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Inibidores de Protease de Coronavírus , Descoberta de Drogas , SARS-CoV-2 , Humanos , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Simulação de Acoplamento Molecular , Inibidores de Protease de Coronavírus/síntese química , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/farmacologia , Relação Estrutura-Atividade , Cristalografia por Raios X
11.
Nature ; 623(7987): 522-530, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37968527

RESUMO

Recreating complex structures and functions of natural organisms in a synthetic form is a long-standing goal for humanity1. The aim is to create actuated systems with high spatial resolutions and complex material arrangements that range from elastic to rigid. Traditional manufacturing processes struggle to fabricate such complex systems2. It remains an open challenge to fabricate functional systems automatically and quickly with a wide range of elastic properties, resolutions, and integrated actuation and sensing channels2,3. We propose an inkjet deposition process called vision-controlled jetting that can create complex systems and robots. Hereby, a scanning system captures the three-dimensional print geometry and enables a digital feedback loop, which eliminates the need for mechanical planarizers. This contactless process allows us to use continuously curing chemistries and, therefore, print a broader range of material families and elastic moduli. The advances in material properties are characterized by standardized tests comparing our printed materials to the state-of-the-art. We directly fabricated a wide range of complex high-resolution composite systems and robots: tendon-driven hands, pneumatically actuated walking manipulators, pumps that mimic a heart and metamaterial structures. Our approach provides an automated, scalable, high-throughput process to manufacture high-resolution, functional multimaterial systems.


Assuntos
Impressão Tridimensional , Robótica , Humanos , Módulo de Elasticidade , Robótica/instrumentação , Robótica/métodos , Retroalimentação , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química
12.
Nature ; 623(7985): 77-82, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37914946

RESUMO

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.


Assuntos
Carbono , Técnicas de Química Sintética , Nitrogênio , Quinazolinas , Quinolinas , Carbono/química , Nitrogênio/química , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/química , Oxirredução , Desenho de Fármacos , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
13.
Nature ; 623(7988): 745-751, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37788684

RESUMO

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.


Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Descarboxilação , Eletroquímica , Eletrodos , Preparações Farmacêuticas , Ácidos Carboxílicos/química , Nanopartículas Metálicas/química , Oxirredução , Prata/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Níquel/química , Ligantes , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Eletroquímica/métodos , Técnicas de Química Sintética/métodos
14.
Int J Mol Sci ; 24(20)2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37894912

RESUMO

Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone-GnRH conjugates (con1-con8) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (con2-con7) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, con3 and con7 show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/síntese química , Antineoplásicos/imunologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Fatores Imunológicos , Terapia de Imunossupressão , Imunossupressores , Mitoxantrona , Neoplasias/tratamento farmacológico , Receptores LHRH/metabolismo
16.
Org Lett ; 25(36): 6618-6622, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37656900

RESUMO

1,4-Dione-containing peptides are generated during the cleavage of 2,5-disubstituted furan-containing systems. The generated electrophilic systems then react with α-effect nucleophiles, following a Paal-Knorr-like mechanism, for the generation of macrocyclic peptides, occurring after simple resuspension of the crude peptide in water. Conveniently, the in situ generation of the electrophile from a stable furan ring avoids the complications associated with the synthesis of carbonyl-containing peptides. Detailed investigation of the reaction characteristics was first performed on supramolecular coiled-coil systems.


Assuntos
Furanos , Cetonas , Domínios Proteicos , Água , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química
17.
Bioorg Chem ; 140: 106796, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37683539

RESUMO

P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (-OCF3, -CF3, and -CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.


Assuntos
Astrocitoma , Hidroxiquinolinas , Antagonistas do Receptor Purinérgico P2X , Quinolinas , Humanos , Apoptose , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores Purinérgicos P2X7 , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/farmacologia
18.
Nature ; 622(7983): 507-513, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37730997

RESUMO

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.


Assuntos
Antineoplásicos , Técnicas de Química Sintética , Iminas , Compostos de Espiro , Humanos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Iminas/síntese química , Iminas/química , Iminas/farmacologia , Neoplasias/tratamento farmacológico , Proteômica , Ribossomos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia
19.
Carbohydr Res ; 533: 108941, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37717483

RESUMO

New fluorinated and nonfluorinated sugar alkenylphosphonates were obtained. In all cases 1,2;5,6-di-O-isopropylidene-α-d-glucofuranose was used as the starting material. The synthesis of alkenylphosphonates was based on Horner-Wadsworth-Emmons olefination. The process led to products with E-stereochemistry exclusively or predominately.


Assuntos
Açúcares , Açúcares/síntese química
20.
Mol Pharm ; 20(10): 5160-5172, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37646101

RESUMO

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pHmax of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13C and 15N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.


Assuntos
Cinarizina , Malatos , Tecnologia Farmacêutica , Água , Varredura Diferencial de Calorimetria , Cinarizina/síntese química , Cinarizina/química , Composição de Medicamentos/métodos , Preparações Farmacêuticas , Sais/síntese química , Cloreto de Sódio , Solubilidade , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X , Malatos/química , Indústria Farmacêutica , Tecnologia Farmacêutica/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...