Late-stage modification of complex drug: Base-controlled Pd-catalyzed regioselective synthesis and bioactivity of arylated osimertinibs.
Sci Adv
; 10(10): eadl0026, 2024 Mar 08.
Article
en En
| MEDLINE
| ID: mdl-38457511
ABSTRACT
Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed CâH arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Paladio
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Pirimidinas
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Acrilamidas
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Compuestos de Anilina
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Neoplasias Pulmonares
Límite:
Animals
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Humans
Idioma:
En
Revista:
Sci Adv
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Estados Unidos