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Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles

Patrick M Kelly1, Sandra A Bright2, Darren Fayne2

  • 1School of Pharmacy & Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.

Bioorganic & Medicinal Chemistry
|July 14, 2016
PubMed

Insights

Novel selective estrogen receptor modulators (SERMs) based on 2-arylindole scaffolds show potent anti-cancer activity against hormone-dependent breast cancer cells. These compounds induce apoptosis with minimal impact on normal cells, offering a promising therapeutic avenue.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Pharmacology

Background:

  • Breast cancer is a leading global cancer, with many early-stage cases being hormone-dependent.
  • Selective Estrogen Receptor Modulators (SERMs) represent a key therapeutic advancement for breast cancer treatment.

Purpose of the Study:

  • To design and synthesize novel SERM-type ligands utilizing the 2-arylindole scaffold.
  • To selectively target the estrogen receptor (ER) in hormone-dependent breast cancers.

Main Methods:

  • Synthesis of novel 2-arylindole derivatives, including bisindole structures and conjugates with combretastatin A4 (CA4).
  • Evaluation of estrogen receptor binding affinity and antiproliferative activity in ER-positive MCF-7 breast cancer cells.
  • Assessment of apoptotic activity and effects on normal peripheral blood cells.

Main Results:

  • Indole compounds 31 and 86 exhibited significant ER binding and potent antiproliferative effects in MCF-7 cells (IC50 values of 2.71μM and 1.86μM, respectively).
  • These active compounds demonstrated induction of apoptosis in MCF-7 cells.
  • Minimal toxicity was observed in normal peripheral blood cells.

Conclusions:

  • Novel 2-arylindole compounds, including bisindoles and CA4 conjugates, show promise as targeted therapies for hormone-dependent breast cancer.
  • Compound 31's efficacy may stem from dual ER binding, while compound 86 combines ER binding with cytotoxic tubulin inhibition.
Keywords:
ApoptosisBreast cancerCombretastatinEstrogen receptorPhenylindoles

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