Published May 2026
| Version Supplemental material
Journal Article
Open
Synthesis of bufalin and digitoxigenin derivatives
Creators
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1.
California Institute of Technology
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2.
Huntington Medical Research Institutes
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3.
University of Southern California
- 4. Alterome Therapeutics, San Diego, CA 92127
Abstract
We report the syntheses of seven novel bufalin derivatives and four digitoxigenin derivatives, inspired by the high affinity of bufalin and digitoxigenin to a ubiquitous enzyme called the Na+, K+–ATPase and their biological potential as brain Na+, K+–ATPase modulators. We sought to design and synthesize derivatives that more closely obey CNS-penetrant guidelines set forth by the medicinal chemistry community compared to their natural product class counterparts, by reducing the number of hydrogen bond donors or acceptors and increasing lipophilicity. In addition, we highlight the necessity of a C14 bulky protecting group in the steroid core to set a desired C17-β stereocenter for the synthesis of C17-β-pyridines or pyridones.
Copyright and License
© 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Acknowledgement
The authors would like to thank the Heritage Medical Research Investigators Program, Huntington Medical Research Institutes (HMRI), and the Boswell family for funding provided by the James G. Boswell postdoctoral fellowship. The authors would also like to thank David VanderVelde for NMR assistance and maintenance of the Caltech NMR facility, Dr. Michael Takase and the Caltech XRD facility for XRD assistance, and Dr. Mona Shahgholi and Dr. Jay Barbor for mass spectrometry assistance.
Contributions
Veronica B. Hubble: Writing – review & editing, Writing – original draft, Resources, Investigation, Formal analysis, Data curation, Conceptualization. Camila A. Suarez: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. Primali V. Navaratne: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Isabel M. de la Torre Roehl: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Alfred N. Fonteh: Supervision, Resources, Project administration. Michael G. Harrington: Supervision, Resources, Project administration, Conceptualization. Michael D. Bartberger: Writing – review & editing, Visualization, Supervision, Investigation, Formal analysis, Data curation, Conceptualization. Scott C. Virgil: Supervision, Investigation, Formal analysis, Data curation. Brian M. Stoltz: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Conceptualization.
Conflict of Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brian M. Stoltz reports financial support was provided by the Heritage Medical Research Investigators Program, Huntington Medical Research Institute (HMRI), and the Boswell family for funding provided by the James G. Boswell postdoctoral scholarship. I, Brian M. Stoltz am Editor in Chief of Tetrahedron, the sister journal to which we are submitting.
Supplemental Material
Supporting Information. General Information, Materials and Methods, Compound characterization for all novel compounds: Nuclear Magnetic Resonance Spectra, 1D NOE Correlations for Compounds S1, 29, 30, and 36. Crystallographic parameters for compound 9 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2495553.
Files
1-s2.0-S0040402025006489-mmc1.pdf
Additional details
Funding
- Huntington Medical Research Institutes
Dates
- Submitted
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2025-11-02
- Accepted
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2025-12-10
- Available
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2025-12-11Available online
- Available
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2026-01-12Version of record
Caltech Custom Metadata
- Caltech groups
- Heritage Medical Research Institute , Division of Chemistry and Chemical Engineering (CCE)
- Publication Status
- Published