Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

Allan M. Prior, Xufen Yu, Eun Jung Park, Tamara P. Kondratyuk, Yan Lin, John M. Pezzuto, Dianqing Sun

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) 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 (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) 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.

Original languageEnglish
Pages (from-to)5393-5399
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number24
DOIs
StatePublished - 15 Dec 2017
Externally publishedYes

Keywords

  • 2-Arylindole
  • Anticancer
  • Aromatase
  • Docking
  • Estrogen
  • Quinone reductase 1

Fingerprint

Dive into the research topics of 'Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1'. Together they form a unique fingerprint.

Cite this