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

Oraphin Chantarasriwong, Andrew T. Milcarek, Theodore Habarth Morales, Aspen L. Settle, Celso O. Rezende, Bashayer D. Althufairi, Maria A. Theodoraki, Mary Alpaugh, Emmanuel A. Theodorakis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)405-413
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
StatePublished - Apr 15 2019

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Inflammatory Breast Neoplasms
Xanthones
Pharmacodynamics
Structure-Activity Relationship
Cytotoxicity
Fluorine
Hydroxyl Radical
Dissolution
Apoptosis
Libraries
Pharmacology
Breast Neoplasms
Therapeutics
In Vitro Techniques
xanthone

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

Cite this

Chantarasriwong, Oraphin ; Milcarek, Andrew T. ; Morales, Theodore Habarth ; Settle, Aspen L. ; Rezende, Celso O. ; Althufairi, Bashayer D. ; Theodoraki, Maria A. ; Alpaugh, Mary ; Theodorakis, Emmanuel A. / Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 168. pp. 405-413.
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Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer. / Chantarasriwong, Oraphin; Milcarek, Andrew T.; Morales, Theodore Habarth; Settle, Aspen L.; Rezende, Celso O.; Althufairi, Bashayer D.; Theodoraki, Maria A.; Alpaugh, Mary; Theodorakis, Emmanuel A.

In: European Journal of Medicinal Chemistry, Vol. 168, 15.04.2019, p. 405-413.

Research output: Contribution to journalArticle

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AU - Morales, Theodore Habarth

AU - Settle, Aspen L.

AU - Rezende, Celso O.

AU - Althufairi, Bashayer D.

AU - Theodoraki, Maria A.

AU - Alpaugh, Mary

AU - Theodorakis, Emmanuel A.

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