Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs).
Angew Chem Int Ed Engl
; 59(50): 22494-22499, 2020 12 07.
Article
em En
| MEDLINE
| ID: mdl-32780485
ABSTRACT
Inhibition of more than one cancer-related pathway by multi-target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well-established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore-linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid-phase-supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ-H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof-of-concept proteolysis-targeting chimera (PROTAC), which efficiently degrades histone deacetylases.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Resinas Sintéticas
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Inibidores de Histona Desacetilases
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Histona Desacetilases
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Ácidos Hidroxâmicos
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article