Isoxazole analogues bind the System xc- transporter: Structure-activity relationship and pharmacophore model

Sarjubhai A. Patel; Trideep Rajale; Erin O'Brien; David J. Burkhart; Jared K. Nelson; Brendan Twamley; Alex Blumenfeld; Monika I. Szabon-Watola; John M. Gerdes; Richard J. Bridges; Nicholas R. Natale

doi:10.1016/j.bmc.2009.11.001

Isoxazole analogues bind the System x_c^- transporter: Structure-activity relationship and pharmacophore model

Sarjubhai A. Patel, Trideep Rajale, Erin O'Brien, David J. Burkhart, Jared K. Nelson, Brendan Twamley, Alex Blumenfeld, Monika I. Szabon-Watola, John M. Gerdes, Richard J. Bridges, Nicholas R. Natale

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

29 Scopus citations

Abstract

Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System x_c^-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System x_c^-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y′ = 3,5-(CF₃)₂, which both inhibited glutamate uptake by the System x_c^- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.

Original language	English
Pages (from-to)	202-213
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.bmc.2009.11.001
State	Published - Jan 1 2010

Funding

The Bruker (Siemens) SMART APEX diffraction facility was established at the University of Idaho with the assistance of the NSF-EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA. The authors thank Drs. C. Sean Esslinger and Mariusz Gajewski for helpful discussions of analogue design. The molecular modeling studies were carried out in the U.M. Molecular Core Computational Facility. This work was supported in part by NIH NINDS NS038444 (N.N.,T.R.), NINDS NS30570 (R.J.B.), NCRR P20RR015583 (R.J.B., N.N., J.G., S.P.), and the Malcolm and Carol Renfrew Scholarship (M.I.S., T.R.).

Funder number
NS038444, R01NS030570
P20RR015583

Keywords

Isoxazole
Pharmacophore
Structure-activity relationship
System x
Transporter

Access to Document

10.1016/j.bmc.2009.11.001

Cite this

Patel, S. A., Rajale, T., O'Brien, E., Burkhart, D. J., Nelson, J. K., Twamley, B., Blumenfeld, A., Szabon-Watola, M. I., Gerdes, J. M., Bridges, R. J., & Natale, N. R. (2010). Isoxazole analogues bind the System x_c^- transporter: Structure-activity relationship and pharmacophore model. Bioorganic and Medicinal Chemistry, 18(1), 202-213. https://doi.org/10.1016/j.bmc.2009.11.001

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abstract = "Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y′ = 3,5-(CF3)2, which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.",

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author = "Patel, \{Sarjubhai A.\} and Trideep Rajale and Erin O'Brien and Burkhart, \{David J.\} and Nelson, \{Jared K.\} and Brendan Twamley and Alex Blumenfeld and Szabon-Watola, \{Monika I.\} and Gerdes, \{John M.\} and Bridges, \{Richard J.\} and Natale, \{Nicholas R.\}",

note = "Funding Information: The Bruker (Siemens) SMART APEX diffraction facility was established at the University of Idaho with the assistance of the NSF-EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA. The authors thank Drs. C. Sean Esslinger and Mariusz Gajewski for helpful discussions of analogue design. The molecular modeling studies were carried out in the U.M. Molecular Core Computational Facility. This work was supported in part by NIH NINDS NS038444 (N.N.,T.R.), NINDS NS30570 (R.J.B.), NCRR P20RR015583 (R.J.B., N.N., J.G., S.P.), and the Malcolm and Carol Renfrew Scholarship (M.I.S., T.R.). ",

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AU - Patel, Sarjubhai A.

AU - Rajale, Trideep

AU - O'Brien, Erin

AU - Burkhart, David J.

AU - Nelson, Jared K.

AU - Twamley, Brendan

AU - Blumenfeld, Alex

AU - Szabon-Watola, Monika I.

AU - Gerdes, John M.

AU - Bridges, Richard J.

AU - Natale, Nicholas R.

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N2 - Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y′ = 3,5-(CF3)2, which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.

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KW - Structure-activity relationship

KW - System x

KW - Transporter

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