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1.
J Org Chem ; 89(10): 6677-6683, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38692583

RESUMO

Unlike secondary alkyl amines and electron-rich anilines, secondary electron-poor anilines are challenging amine sources to explore the chemical space of Lewis acid-catalyzed condensation-based transformations with furfural. In this work, we report the efficient synthesis of trans-4,5-diamino cyclopentenones (DCP) using a high-pressure promoted Nazarov-like electrocyclization of Stenhouse salts arising from the Sc(III)-catalyzed condensation of furfural with secondary electron-poor anilines. The reaction enables access to otherwise difficult-to-access DCP and compatibility with a large scope of alkyl and aryl secondary amines. A 2- to 18-fold increase in yields for electron-poor anilines was highlighted using this approach in the synthesis of a pharmacologically active compound.

2.
J Am Chem Soc ; 142(9): 4235-4241, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32057243

RESUMO

Inverse-electron demand Diels-Alder cycloadditions have emerged as important bioorthogonal reactions in chemical biology. Understanding and predicting reaction rates for bioconjugation reactions is fundamental for evaluating their efficacy in biological systems. Here, we present multivariate models to predict the second order rate constants of bioorthogonal inverse-electron demand Diels-Alder reactions involving 1,2,4,5-tetrazines derivatives. A data-driven approach was used to model these reactions by parametrizing both the dienophiles and the dienes partners. The models are statistically robust and were used to predict/extrapolate the outcome of several reactions as well as to identify mechanistic differences among similar reactants.


Assuntos
Alcenos/química , Compostos Heterocíclicos com 1 Anel/química , Reação de Cicloadição , Cinética , Modelos Químicos
3.
Chemistry ; 25(1): 43-59, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30095185

RESUMO

Maleimide chemistry stands out in the bioconjugation toolbox by virtue of its synthetic accessibility, excellent reactivity, and practicability. The second-generation of clinically approved antibody-drug conjugates (ADC) and much of the current ADC pipeline in clinical trials contain the maleimide linkage. However, thiosuccinimide linkages are now known to be less robust than once thought, and ergo, are correlated with suboptimal pharmacodynamics, pharmacokinetics, and safety profiles in some ADC constructs. Rational design of novel generations of maleimides and maleimide-type reagents have been reported to address the shortcomings of classical maleimides, allowing for the formation of robust bioconjugate linkages. This review highlights the main strategies for rational reagent design that have allowed irreversible bioconjugations in cysteines, reversible labelling strategies and disulfide re-bridging.


Assuntos
Imunoconjugados/química , Maleimidas/química , Anticorpos/química , Anticorpos/metabolismo , Humanos , Imunoconjugados/metabolismo , Maleimidas/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Somatostatina/química , Somatostatina/metabolismo , Compostos de Sulfidrila/química
4.
Nat Nanotechnol ; 19(6): 867-878, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38750164

RESUMO

Owing to their distinct physical and chemical properties, inorganic nanoparticles (NPs) have shown promising results in preclinical cancer therapy, but designing and engineering them for effective therapeutic purposes remains a challenge. Although a comprehensive database of inorganic NP research is not currently available, it is crucial for developing effective cancer therapies. In this context, machine learning (ML) has emerged as a transformative tool, but its adaptation to nanomedicine is hindered by inexistent or small datasets. Here we assembled a large database of inorganic NPs, comprising experimental datasets from 745 preclinical studies in cancer nanomedicine. Using descriptive statistics and explainable ML models we mined this database to gain knowledge of inorganic NP design patterns and inform future NP research for cancer treatment. Our analyses suggest that NP shape and therapy type are prominent features in determining in vivo efficacy, measured as a percentage of tumour reduction. Moreover, our database provides a large-scale open-access resource for discriminative ML that the broader nanotechnology community can utilize. Our work blueprints data mining for translational cancer research and offers evidence for standardizing NP reporting to accelerate and de-risk inorganic NP-based drug delivery, which may help to improve patient outcomes in clinical settings.


Assuntos
Aprendizado de Máquina , Nanomedicina , Nanopartículas , Neoplasias , Nanopartículas/química , Humanos , Neoplasias/tratamento farmacológico , Animais , Nanomedicina/métodos , Camundongos , Bases de Dados Factuais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem
5.
ChemSusChem ; 15(13): e202102204, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35040553

RESUMO

The creation of structurally diverse chemical entities from fairly simple biorefinery products remains a challenge. In this work 5-hydroxymethylfurfural (HMF) was identified as a key synthon for preparing highly complex cyclopentenones (CP) via tandem 1,4-addition/elimination/remote lactone activation to external O- and N-nucleophiles in δ-lactone-fused-CPs hotspots. This scaffold was also reactive enough to be incorporated into model cysteine-peptides in low concentrations, paving the way to a potential translation generating complexity in the synthesis of small peptides. The new enones also exhibited activity against intraerythrocytic Plasmodium falciparum (IC50 =1.32 µm).


Assuntos
Furanos , Lactonas , Ciclopentanos , Furaldeído/análogos & derivados
6.
ChemSusChem ; 14(15): 3047-3053, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34058082

RESUMO

The preparation of high value-added chemicals from renewable resources is a crucial approach towards a sustainable economy. One prominent alternative to the production of petroleum-based chemicals from fossil resources is through the sequential Diels-Alder/aromatization reactions of biomass-derived furan platforms. This Concept is focused on the recent boom in bio-based furan DA strategies for aromatization of bio-based platform chemicals, particularly that of furfurals, ranging from indirect use and activation strategies to recent examples of direct DA reaction of these electron-withdrawing biomass-derived furans.

7.
ChemSusChem ; 12(20): 4629-4635, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31531965

RESUMO

A new chemoselective (enzymatic desymmetrization/Ru-catalyzed C-H activation) sequence to obtain differently substituted furans from the largely available 2,5-furandicarboxylic acid (FDCA) was developed. Series of di- and trisubstituted furans were prepared in very good yields and excellent chemoselectivity. This study discloses a new approach towards valorization of the furanics platform through the use of FDCA as a stable intermediate, thus circumventing the chemical instability of the parent 5-hydroxymethylfurfural.

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