Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1.
Bioorg Med Chem Lett
; 27(24): 5393-5399, 2017 12 15.
Article
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| MEDLINE
| ID: mdl-29153737
ABSTRACT
In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50â¯=â¯1.61⯵M; 21, IC50â¯=â¯3.05⯵M; and 27, IC50â¯=â¯3.34⯵M) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IRâ¯=â¯8.34, CDâ¯=â¯2.75⯵M), while 7 showed the most potent CD value of 1.12⯵M. A dual acting compound 24 showed aromatase inhibition (IC50â¯=â¯9.00⯵M) as well as QR1 induction (CDâ¯=â¯5.76⯵M) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Aromatasa
/
NAD(P)H Deshidrogenasa (Quinona)
/
Inhibidores de la Aromatasa
/
Indoles
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos