10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties

Matthew J. Weaver; Sascha Stump; Michael J. Campbell; Donald S. Backos; Chun Li; Philip Reigan; Earle Adams; Howard D. Beall; Nicholas R. Natale

doi:10.1016/j.bmc.2020.115781

10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties

Matthew J. Weaver
, Sascha Stump
, Michael J. Campbell
, Donald S. Backos
, Chun Li
, Philip Reigan
, Earle Adams
, Howard D. Beall
, Nicholas R. Natale

University of Montana
Nutritional Services
University of Colorado Anschutz Medical Campus
Ithaca College

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

7 Scopus citations

Abstract

A novel series of anthracenyl-isoxazole amide (AIM) antitumor agents containing N-heterocycles in the 10 position (N-het) were synthesized using palladium cross-coupling. The unique steric environment of the N-het-AIMs required individual optimization in each case. Lanthanide mediated double activation was used to couple the dimethylamino pyrrole moiety, required for antitumor action. Robust antitumor activity was observed against breast and brain cancer cell lines. The compounds were docked with the c-myc oncogene promoter sequence, which adopts a G4 quadruplex DNA conformation, and represents the working hypothesis for biological action. The N-het-AIMs have useful fluorescence properties, allowing for observation of their distribution within tumor cells.

Original language	English
Article number	115781
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	22
DOIs	https://doi.org/10.1016/j.bmc.2020.115781
State	Published - Nov 15 2020

Funding

The authors thank the ALSAM Foundation for support of this work. W e thank Dan DeCato for small molecule crystallography of 2c and 2e performed by the small molecule x-ray core, supported by National Science Foundation (NSF)-MRI (CHE - 1337908), and National Institutes of Health (CoBRE NIGMS P20GM103546). We thank Professor Bruce Bowler for use of his CD. We thank Dr. Kevin Rider for helpful discussions on isoxazole poisoning of palladium cross-couplings, and Christina Gates for help in HPLC-MS.

Funder number
P20GM103546
CHE - 1337908

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.bmc.2020.115781

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Weaver, M. J., Stump, S., Campbell, M. J., Backos, D. S., Li, C., Reigan, P., Adams, E., Beall, H. D., & Natale, N. R. (2020). 10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties. Bioorganic and Medicinal Chemistry, 28(22), Article 115781. https://doi.org/10.1016/j.bmc.2020.115781

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title = "10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties",

abstract = "A novel series of anthracenyl-isoxazole amide (AIM) antitumor agents containing N-heterocycles in the 10 position (N-het) were synthesized using palladium cross-coupling. The unique steric environment of the N-het-AIMs required individual optimization in each case. Lanthanide mediated double activation was used to couple the dimethylamino pyrrole moiety, required for antitumor action. Robust antitumor activity was observed against breast and brain cancer cell lines. The compounds were docked with the c-myc oncogene promoter sequence, which adopts a G4 quadruplex DNA conformation, and represents the working hypothesis for biological action. The N-het-AIMs have useful fluorescence properties, allowing for observation of their distribution within tumor cells.",

author = "Weaver, \{Matthew J.\} and Sascha Stump and Campbell, \{Michael J.\} and Backos, \{Donald S.\} and Chun Li and Philip Reigan and Earle Adams and Beall, \{Howard D.\} and Natale, \{Nicholas R.\}",

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AU - Weaver, Matthew J.

AU - Stump, Sascha

AU - Campbell, Michael J.

AU - Backos, Donald S.

AU - Li, Chun

AU - Reigan, Philip

AU - Adams, Earle

AU - Beall, Howard D.

AU - Natale, Nicholas R.

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N2 - A novel series of anthracenyl-isoxazole amide (AIM) antitumor agents containing N-heterocycles in the 10 position (N-het) were synthesized using palladium cross-coupling. The unique steric environment of the N-het-AIMs required individual optimization in each case. Lanthanide mediated double activation was used to couple the dimethylamino pyrrole moiety, required for antitumor action. Robust antitumor activity was observed against breast and brain cancer cell lines. The compounds were docked with the c-myc oncogene promoter sequence, which adopts a G4 quadruplex DNA conformation, and represents the working hypothesis for biological action. The N-het-AIMs have useful fluorescence properties, allowing for observation of their distribution within tumor cells.

AB - A novel series of anthracenyl-isoxazole amide (AIM) antitumor agents containing N-heterocycles in the 10 position (N-het) were synthesized using palladium cross-coupling. The unique steric environment of the N-het-AIMs required individual optimization in each case. Lanthanide mediated double activation was used to couple the dimethylamino pyrrole moiety, required for antitumor action. Robust antitumor activity was observed against breast and brain cancer cell lines. The compounds were docked with the c-myc oncogene promoter sequence, which adopts a G4 quadruplex DNA conformation, and represents the working hypothesis for biological action. The N-het-AIMs have useful fluorescence properties, allowing for observation of their distribution within tumor cells.

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DO - 10.1016/j.bmc.2020.115781

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M1 - 115781

ER -

10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties

Abstract

Funding

UN SDGs

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