10-Alkoxy-anthracenyl-isoxazole analogs have sub-micromolar activity against a Glioblastoma multiforme cell line

Nathan S. Duncan; Michael J. Campbell; Donald S. Backos; Chun Li; Kevin C. Rider; Sascha Stump; Matthew J. Weaver; Mariusz P. Gajewski; Howard D. Beall; Philip Reigan; Nicholas R. Natale

doi:10.1016/j.bmc.2022.116911

10-Alkoxy-anthracenyl-isoxazole analogs have sub-micromolar activity against a Glioblastoma multiforme cell line

Nathan S. Duncan, Michael J. Campbell, Donald S. Backos, Chun Li, Kevin C. Rider, Sascha Stump, Matthew J. Weaver, Mariusz P. Gajewski, Howard D. Beall, Philip Reigan, Nicholas R. Natale

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5 Scopus citations

Abstract

A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. The novel RO-AIMs described here exhibit robust growth inhibition for the human SNB19 CNS glioblastoma cell line, and biphenyl analog 8c had activity in the nanomolar regime, which represents the most efficacious compound in the AIM series to date. Computational modeling for RO-AIMs binding in a ternary complex with c-myc quadruplex DNA and its helicase DHX36 is presented which represents our current working hypothesis.

Original language	English
Article number	116911
Journal	Bioorganic and Medicinal Chemistry
Volume	69
DOIs	https://doi.org/10.1016/j.bmc.2022.116911
State	Published - Sep 1 2022

Funding

The authors (DSB, HDB, NRN, PR) thank the ALSAM foundation for a Skaggs Scholar Grant, and the NIH/NIEHS for P20RR017670 (HDB). NSD thanks the Medicinal Chemistry Division of the American Chemical Society for support to present this work at the Denver National meeting in 2015, abstract MEDI # 316. NRN thanks coauthors PR and DSB for access to the computational facilities at the Anschutz Medical campus during his sabbatical leave, supported by NIH/NCATS UL1 TR001082 (DSB, PR). We thank Dan Decato for solving the sc-xrd of intermediate 12 , and support from the National Science Foundation (NSF)-MRI (CHE - 1337908) to obtain the instrument. The authors (DSB, HDB, NRN, PR) thank the ALSAM foundation for a Skaggs Scholar Grant, and the NIH/NIEHS for P20RR017670 (HDB). NSD thanks the Medicinal Chemistry Division of the American Chemical Society for support to present this work at the Denver National meeting in 2015, abstract MEDI # 316. NRN thanks coauthors PR and DSB for access to the computational facilities at the Anschutz Medical campus during his sabbatical leave, supported by NIH/NCATS UL1 TR001082 (DSB, PR). We thank Dan Decato for solving the sc-xrd of intermediate 12, and support from the National Science Foundation (NSF)-MRI (CHE - 1337908) to obtain the instrument.

Funders	Funder number
P20RR017670
American Chemical Society	316
UL1 TR001082
CHE - 1337908

Keywords

Anti-tumor
Isoxazole
Pyrrole
Quadruplex DNA
Synthesis

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10.1016/j.bmc.2022.116911

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Duncan, N. S., Campbell, M. J., Backos, D. S., Li, C., Rider, K. C., Stump, S., Weaver, M. J., Gajewski, M. P., Beall, H. D., Reigan, P., & Natale, N. R. (2022). 10-Alkoxy-anthracenyl-isoxazole analogs have sub-micromolar activity against a Glioblastoma multiforme cell line. Bioorganic and Medicinal Chemistry, 69, Article 116911. https://doi.org/10.1016/j.bmc.2022.116911

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abstract = "A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. The novel RO-AIMs described here exhibit robust growth inhibition for the human SNB19 CNS glioblastoma cell line, and biphenyl analog 8c had activity in the nanomolar regime, which represents the most efficacious compound in the AIM series to date. Computational modeling for RO-AIMs binding in a ternary complex with c-myc quadruplex DNA and its helicase DHX36 is presented which represents our current working hypothesis.",

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AU - Duncan, Nathan S.

AU - Campbell, Michael J.

AU - Backos, Donald S.

AU - Li, Chun

AU - Rider, Kevin C.

AU - Stump, Sascha

AU - Weaver, Matthew J.

AU - Gajewski, Mariusz P.

AU - Beall, Howard D.

AU - Reigan, Philip

AU - Natale, Nicholas R.

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AB - A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. The novel RO-AIMs described here exhibit robust growth inhibition for the human SNB19 CNS glioblastoma cell line, and biphenyl analog 8c had activity in the nanomolar regime, which represents the most efficacious compound in the AIM series to date. Computational modeling for RO-AIMs binding in a ternary complex with c-myc quadruplex DNA and its helicase DHX36 is presented which represents our current working hypothesis.

KW - Anti-tumor

KW - Isoxazole

KW - Pyrrole

KW - Quadruplex DNA

KW - Synthesis

UR - https://www.scopus.com/pages/publications/85133238331

U2 - 10.1016/j.bmc.2022.116911

DO - 10.1016/j.bmc.2022.116911

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AN - SCOPUS:85133238331

SN - 0968-0896

VL - 69

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 116911

ER -

10-Alkoxy-anthracenyl-isoxazole analogs have sub-micromolar activity against a Glioblastoma multiforme cell line

Abstract

Funding

Keywords

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