Enantioselective Synthesis and Biological Evaluation of Sanglifehrinâ
A and B and Analogs.
Angew Chem Int Ed Engl
; 60(31): 17045-17052, 2021 07 26.
Article
em En
| MEDLINE
| ID: mdl-34014025
Sanglifehrinâ
A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrinâ
A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo-controlled spirocyclization. The 22-membered macrocyclic core was synthesized by ring-closing metathesis in the presence of 2,6-bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrinâ
A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the 2-CF3 analog of sanglifehrin B exhibited higher anti-proliferative activity than the natural products sanglifehrinâ
A and B in Jurkat cells. Both natural products induced higher-order homodimerization of cyclophilinâ
A (CypA), but only sanglifehrinâ
A promoted CypA complexation with inosine-5'-monophosphate dehydrogenaseâ
2 (IMPDH2). The synthesis reported herein will enable further evaluation of the spirolactam and its contribution to sanglifehrin-dependent immunosuppressive activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunossupressores
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Alemanha