Development of Potent Microtubule Targeting Agent by Structural Simplification of Natural Diazonamide.
J Med Chem
; 67(11): 9227-9259, 2024 Jun 13.
Article
em En
| MEDLINE
| ID: mdl-38833507
ABSTRACT
The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (991 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Moduladores de Tubulina
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Microtúbulos
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article