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Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes.

Maria Grazia Perrone1, Paola Vitale1, Morena Miciaccia1

  • 1Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.

Pharmaceuticals (Basel, Switzerland)
|June 24, 2022
PubMed
Summary

New fluorescent compounds targeting cyclooxygenase (COX)-1 were synthesized for ovarian cancer. These potent COX-1 inhibitors showed tumor-specific signals in preclinical models, offering potential for improved diagnostics and therapeutics.

Keywords:
COX-1 and COX-2 selective inhibitorsfluorescent probesmofezolacovarian cancertumor-targeted imaging

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Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Biotechnology

Background:

  • Ovarian cancer treatment faces challenges in complete tumor removal, with residual disease negatively impacting prognosis.
  • Cyclooxygenase (COX)-1 is identified as an ovarian cancer biomarker, making it a potential therapeutic target.

Purpose of the Study:

  • To synthesize and evaluate novel compounds as selective cyclooxygenase (COX)-1 inhibitors for ovarian cancer.
  • To investigate the potential of these compounds as fluorescent probes for imaging ovarian cancer xenografts.

Main Methods:

  • Synthesis of fluorochrome-bearing compounds designed as COX-1 inhibitors.
  • In vitro evaluation of inhibitory activity and selectivity against COX-1 and COX-2 isoforms.
  • Structure-based virtual screening (SBVS) using Fingerprints for Ligands and Proteins (FLAP) software.
  • Preliminary near-infrared (NIR) fluorescent imaging (FLI) in human ovarian cancer xenograft models.

Main Results:

  • Two compounds, RR11 and 23 (MSA14), demonstrated potent and selective inhibition of COX-1 in vitro (IC50 values of 0.032 and 0.087 µM, respectively).
  • High selectivity indices (75 for RR11, 874 for 23 (MSA14)) were achieved, with minimal to no inhibition of COX-2.
  • SBVS successfully predicted compound activity and elucidated interactions within the hCOX1 binding cavity.
  • Both RR11 and 23 (MSA14) exhibited surprising tumor-specific signals in preclinical ovarian cancer models via FLI, independent of COX-1 presence.

Conclusions:

  • Novel fluorochrome-conjugated compounds are potent and selective COX-1 inhibitors.
  • These compounds show promise as diagnostic tools for ovarian cancer imaging, exhibiting tumor-specific fluorescence.
  • Further investigation is warranted to understand the mechanism of tumor-specific signaling and therapeutic potential.