Structural simplification of evodiamine: Discovery of novel tetrahydro-ß-carboline derivatives as potent antitumor agents.
Bioorg Med Chem Lett
; 40: 127954, 2021 05 15.
Article
en En
| MEDLINE
| ID: mdl-33744440
ABSTRACT
Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-ß-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Carbolinas
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Inhibidores de Topoisomerasa I
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Inhibidores de Topoisomerasa II
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Neoplasias
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Antineoplásicos
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
China