Facile synthesis of 1,2-dione-containing abietane analogues for the generation of human carboxylesterase inhibitors.
Eur J Med Chem
; 149: 79-89, 2018 Apr 10.
Article
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| MEDLINE
| ID: mdl-29499489
Recently, a series of selective human carboxylesterase inhibitors have been identified based upon the tanshinones, with biologically active molecules containing a 1,2-dione group as part of a naphthoquinone core. Unfortunately, the synthesis of such compounds is complex. Here we describe a novel method for the generation of 1,2-dione containing diterpenoids using a unified approach, by which boronic acids are joined to vinyl bromo-cyclohexene derivatives via Suzuki coupling, followed by electrocyclization and oxidation to the o-phenanthroquinones. This has allowed the construction of a panel of miltirone analogues containing an array of substituents (methyl, isopropyl, fluorine, methoxy) which have been used to develop preliminary SAR with the two human carboxylesterase isoforms. As a consequence, we have synthesized highly potent inhibitors of these enzymes (Kiâ¯<â¯15â¯nM), that maintain the core tanshinone scaffold. Hence, we have developed a facile and reproducible method for the synthesis of abietane analogues that have resulted in a panel of miltirone derivatives that will be useful tool compounds to assess carboxylesterase biology.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenantrenos
/
Abietanos
/
Carboxilesterasa
/
Técnicas de Química Sintética
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Francia