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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Published on: May 28, 2014

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Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship

Amanda J Pickard1, Fang Liu, Thomas F Bartenstein

  • 1Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109 (USA).

Chemistry (Weinheim an Der Bergstrasse, Germany)
|October 11, 2014
PubMed

Insights

New platinum-acridine hybrids show promise for chemoresistant non-small cell lung cancer (NSCLC). A modified agent, P1-B1, demonstrates potent anticancer activity with significantly reduced toxicity and genotoxicity compared to earlier versions.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Pharmacology

Background:

  • Platinum-acridine hybrid agents exhibit potent activity against chemoresistant non-small cell lung cancer (NSCLC).
  • However, these agents display significant systemic toxicity and promiscuous genotoxicity in vivo, limiting their therapeutic potential.

Purpose of the Study:

  • To develop novel platinum-acridine hybrid agents with improved pharmacological properties and reduced toxicity.
  • To identify promising scaffolds for more selective and tolerable NSCLC therapeutics.

Main Methods:

  • A modular build-click-screen approach was employed to synthesize and evaluate a library of twenty hybrid agents.
  • Selected derivatives were tested in five NSCLC cell lines, and their in vivo tolerability was assessed in mice.
  • Mechanistic studies included cellular distribution, DNA/RNA adduct formation, and G-quadruplex DNA binding analysis.

Main Results:

  • A 7-aminobenz[c]acridine-based hybrid agent (P1-B1) maintained submicromolar activity against DNA-repair proficient and p53-mutant NSCLC models.
  • P1-B1 demonstrated a 32-fold improvement in tolerability in mice compared to the parent compound (P1-A1).
  • Cellular studies indicated reduced DNA/RNA adduct formation and potential for selective G-quadruplex DNA binding for P1-B1.

Conclusions:

  • The 7-aminobenz[c]acridine scaffold offers a promising basis for developing less genotoxic and more tolerable platinum-based anticancer agents.
  • P1-B1 represents a potential therapeutic candidate for chemoresistant NSCLC with an improved safety profile and enhanced target selectivity.
Keywords:
DNA adductsanticancer drugscellular targetcytotoxicityintercalation

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