Synthesis of bufalin and digitoxigenin derivatives

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. ; © 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies. ; 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. ; 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, ...