Synthesis and evaluation of the anti-proliferative and NF-κB activities of a library of simplified tylophorine analogs

Micah J. Niphakis, Bryant C. Gay, Kwon Ho Hong, Nicholas P. Bleeker, Gunda I. Georg

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2, 3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.

Original languageEnglish (US)
Pages (from-to)5893-5900
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number19
DOIs
StatePublished - Oct 1 2012

Bibliographical note

Funding Information:
This work was supported by the University of Minnesota through the Vince and McKnight Endowed Chairs (to GIG) and an ACS Division of Medicinal Chemistry Predoctoral Fellowship (to M. J. N).

Keywords

  • Cytotoxicity
  • Phenanthropiperidine
  • Simplified analogs
  • Synthesis
  • Tylophorine

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