2. Academic Validation
  3. Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

  • Eur J Med Chem. 2019 Apr 15:168:405-413. doi: 10.1016/j.ejmech.2019.02.047.
Oraphin Chantarasriwong 1,  Andrew T Milcarek 2,  Theodore Habarth Morales 3,  Aspen L Settle 3,  Celso O Rezende Jr 4,  Bashayer D Althufairi 4,  Maria A Theodoraki 5,  Mary L Alpaugh 6,  Emmanuel A Theodorakis 7
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0358, USA; Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, 126 Pracha Uthit Rd., Bang Mod, Thung Khru, Bangkok, 10140, Thailand.
  • 2 Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, NJ, 08028, USA.
  • 3 Department of Biology, Arcadia University, Glenside, PA, 19038, USA.
  • 4 Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0358, USA.
  • 5 Department of Biology, Arcadia University, Glenside, PA, 19038, USA. Electronic address: theodorakim@arcadia.edu.
  • 6 Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, NJ, 08028, USA. Electronic address: alpaugh@rowan.edu.
  • 7 Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0358, USA. Electronic address: etheodorakis@ucsd.edu.
PMID: 30831408 DOI: 10.1016/j.ejmech.2019.02.047
Abstract

Inflammatory breast Cancer (IBC) is a highly metastatic, lethal form of breast Cancer that lacks targeted therapeutic strategies. Inspired by the promising cytotoxicity of gambogic acid and related caged Xanthones in spheroidsMARY-X, an in vitro preclinical IBC model, we constructed a library of synthetic analogs and performed structure-activity relationship studies. The studies revealed that functionalizing the A-ring of the caged xanthone framework can significantly affect potency. Specifically, introduction of hydroxyl or fluorine groups at discrete positions of the A-ring leads to enhanced cytotoxicity at submicromolar concentrations. These compounds induce complete dissolution of spheroidsMARY-X with subsequent Apoptosis of both the peripherally- and centrally-located cells, proliferative and quiescent-prone (e.g. hypoxic), respectively. These results highlight the structural flexibility and pharmacological potential of the caged xanthone motif for the design of IBC-targeting therapeutics.

Keywords

Apoptosis; Breast cancer; Natural product; Spheroids; Synthetic methods.

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