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Substituted Tetrahydroisoquinolines as Microtubule-destabilizing Agents in Triple Negative Human Breast Cancer Cells

Madhavi Gangapuram1, Riccardo Jean1, Elizabeth Mazzio1

  • 1College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.

Anticancer Research
|November 1, 2016
PubMed

Insights

New tetrahydroisoquinoline (THIQ) compounds show promise as triple-negative breast cancer (TNBC) therapeutics. These THIQs halt TNBC cell proliferation by disrupting microtubule networks, independent of hormone receptors.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Cell Biology

Background:

  • Triple-negative breast cancer (TNBC) disproportionately affects African-Americans and lacks targeted therapies.
  • Current TNBC treatments include cytotoxic agents, but novel therapeutic strategies are needed.
  • Tetrahydroisoquinolines (THIQs) are a class of compounds with potential pharmacological activity.

Purpose of the Study:

  • To synthesize novel substituted tetrahydroisoquinoline (THIQ) moieties.
  • To evaluate the in vitro efficacy of synthesized THIQs against triple-negative breast cancer (TNBC) cells.
  • To elucidate the mechanism of action of promising THIQ compounds in TNBC.

Main Methods:

  • Synthesis of THIQs via N-amination of substituted isoquinolines, followed by ylide formation and reduction.
  • In vitro evaluation using differential scatter plots to assess ER modulation in MCF-7 and MDA-MB-231 cells.
  • Assays to determine antiproliferative effects, cell cycle arrest (G2 phase), DNA synthesis inhibition, and microtubule dynamics.

Main Results:

  • Successful synthesis of substituted THIQs in moderate to good yields.
  • Two lead THIQ compounds (GM-4-53 and GM-3-121) exhibited potent cytostatic effects on TNBC cells (MDA-MB-231) with IC50 < 2.5 μM.
  • These compounds induced mitotic arrest, inhibited DNA replication, disrupted microtubule polymerization, and caused multinucleation, acting independently of the estrogen receptor (ER).

Conclusions:

  • Specific THIQs possess significant antiproliferative activity against TNBC cells.
  • The mechanism involves direct interference with microtubule dynamics, leading to cell cycle arrest at the G2 phase.
  • THIQs represent a potential new class of ER-independent therapeutics for TNBC, warranting further investigation for safety and efficacy, including combination therapy with taxanes.
Keywords:
Triple-negative breast cancertaxanestetrahydroisoquinolines

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