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 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

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

Biological Sciences

Rowan University

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	405-413
Number of pages	9
Journal	European Journal of Medicinal Chemistry
Volume	168
DOIs	https://doi.org/10.1016/j.ejmech.2019.02.047
State	Published - Apr 15 2019

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2019.02.047

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Chantarasriwong, O., Milcarek, A. T., Morales, T. H., Settle, A. L., Rezende, C. O., Althufairi, B. D., Theodoraki, M. A., Alpaugh, M. L., & Theodorakis, E. A. (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. https://doi.org/10.1016/j.ejmech.2019.02.047

@article{57e75989e7404096bcc2df7c3f4a9021,

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

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.",

author = "Oraphin Chantarasriwong and Milcarek, \{Andrew T.\} and Morales, \{Theodore Habarth\} and Settle, \{Aspen L.\} and Rezende, \{Celso O.\} and Althufairi, \{Bashayer D.\} and Theodoraki, \{Maria A.\} and Alpaugh, \{Mary L.\} and Theodorakis, \{Emmanuel A.\}",

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year = "2019",

month = apr,

day = "15",

doi = "10.1016/j.ejmech.2019.02.047",

language = "English (US)",

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Chantarasriwong, O, Milcarek, AT, Morales, TH, Settle, AL, Rezende, CO, Althufairi, BD, Theodoraki, MA, Alpaugh, ML & Theodorakis, EA 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, vol. 168, pp. 405-413. https://doi.org/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. / Chantarasriwong, Oraphin; Milcarek, Andrew T.; Morales, Theodore Habarth et al.
In: European Journal of Medicinal Chemistry, Vol. 168, 15.04.2019, p. 405-413.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

AU - Chantarasriwong, Oraphin

AU - Milcarek, Andrew T.

AU - Morales, Theodore Habarth

AU - Settle, Aspen L.

AU - Rezende, Celso O.

AU - Althufairi, Bashayer D.

AU - Theodoraki, Maria A.

AU - Alpaugh, Mary L.

AU - Theodorakis, Emmanuel A.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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.

AB - 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.

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DO - 10.1016/j.ejmech.2019.02.047

M3 - Article

C2 - 30831408

SN - 0223-5234

VL - 168

SP - 405

EP - 413

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

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