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 Jr; Bashayer D Althufairi; Maria A Theodoraki; Mary L Alpaugh; Emmanuel A Theodorakis

doi:10.1016/j.ejmech.2019.02.047

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. Epub 2019 Feb 20.

Authors

Oraphin Chantarasriwong¹, Andrew T Milcarek², Theodore Habarth Morales³, Aspen L Settle³, Celso O Rezende Jr⁴, Bashayer D Althufairi⁴, Maria A Theodoraki⁵, Mary L Alpaugh⁶, Emmanuel A Theodorakis⁷

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: [email protected].
⁶ Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, NJ, 08028, USA. Electronic address: [email protected].
⁷ Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0358, USA. Electronic address: [email protected].

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 spheroids^MARY-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 spheroids^MARY-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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Inflammatory Breast Neoplasms / drug therapy*
Inflammatory Breast Neoplasms / pathology
Molecular Structure
Structure-Activity Relationship
Xanthones / chemical synthesis
Xanthones / chemistry
Xanthones / pharmacology*

Substances

Antineoplastic Agents
Xanthones