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1.
Chemistry ; 29(5): e202300069, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36692211

RESUMO

Invited for the cover of this issue are the groups of Professors Passarella and Pieraccini at the University of Milan, in collaboration with some of the members of TubInTrain consortium. The image depicts work with the elements of nature, in particular the destabilising effect of maytansinol (the constellation) on microtubules (the trees). Read the full text of the article at 10.1002/chem.202203431.


Assuntos
Maitansina , Microtúbulos , Pesquisa , Grupo Social
2.
Chemistry ; 29(5): e202203431, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36468686

RESUMO

Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long-chain derivatives and maytansinoid conjugates. We confirmed that bulky substituents do not impact their high activity or the scaffold's binding mode. These encouraging results open new avenues for the design of new maytansine-based probes.


Assuntos
Antineoplásicos , Maitansina , Tubulina (Proteína)/metabolismo , Antineoplásicos/metabolismo , Microtúbulos
3.
Chemistry ; 28(2): e202103520, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34788896

RESUMO

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders.


Assuntos
Maitansina , Neoplasias , Humanos , Maitansina/análogos & derivados , Microtúbulos , Tubulina (Proteína) , Moduladores de Tubulina
4.
Chem Sci ; 15(11): 3879-3892, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38487227

RESUMO

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

5.
Drug Discov Today ; 26(2): 604-615, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33279455

RESUMO

The association of microtubule (MT) breakdown with neurodegeneration and neurotoxicity has provided an emerging therapeutic approach for neurodegenerative diseases. Tubulin binders are able to modulate MT dynamics and, as a result, are of particular interest both as potential therapeutics and experimental tools used to validate this strategy. Here, we provide a comprehensive overview of current knowledge and recent advancements regarding MT-targeting approaches for neurodegeneration and evaluate the potential application of MT-targeting agents (MTAs) based on available preclinical and clinical data.


Assuntos
Desenvolvimento de Medicamentos/métodos , Microtúbulos/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Humanos , Microtúbulos/metabolismo , Terapia de Alvo Molecular , Doenças Neurodegenerativas/fisiopatologia
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