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

Autor: Mary L. Alpaugh, Aspen L. Settle, Maria A. Theodoraki, Andrew T. Milcarek, Bashayer D. Althufairi, Oraphin Chantarasriwong, Theodore Habarth Morales, Emmanuel A. Theodorakis, Celso O. Rezende
Rok vydání: 2019
Předmět:
Medicinal & Biomolecular Chemistry
Xanthones
Antineoplastic Agents
Apoptosis
Breast Neoplasms
Pharmacology
01 natural sciences
Inflammatory breast cancer
Natural product
03 medical and health sciences
chemistry.chemical_compound
Medicinal and Biomolecular Chemistry
Structure-Activity Relationship
Breast cancer
Synthetic methods
Drug Discovery
Xanthone
medicine
Structure–activity relationship
Humans
Cytotoxicity
skin and connective tissue diseases
030304 developmental biology
Cell Proliferation
0303 health sciences
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
General Medicine
Pharmacology and Pharmaceutical Sciences
medicine.disease
In vitro
0104 chemical sciences
chemistry
Gambogic acid
Female
Inflammatory Breast Neoplasms
Spheroids
Drug Screening Assays
Antitumor
Zdroj: Chantarasriwong, Oraphin; Milcarek, Andrew T; Morales, Theodore Habarth; Settle, Aspen L; Rezende, Celso O; Althufairi, Bashayer D; et al.(2019). Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer.. European journal of medicinal chemistry, 168, 405-413. doi: 10.1016/j.ejmech.2019.02.047. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/70s1j4tz
ISSN: 1768-3254
DOI: 10.1016/j.ejmech.2019.02.047.
Popis: 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.
Databáze: OpenAIRE
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