5,10b-Ethanophenanthridine amaryllidaceae alkaloids inspire the discovery of novel bicyclic ring systems with activity against drug resistant cancer cells

Sean Henry, Ria Kidner, Mary R. Reisenauer, Igor V. Magedov, Robert Kiss, Véronique Mathieu, Florence Lefranc, Ramesh Dasari, Antonio Evidente, Xiaojie Yu, Xiuye Ma, Alexander Pertsemlidis, Regina Cencic, Jerry Pelletier, David A. Cavazos, Andrew J. Brenner, Alexander V. Aksenov, Snezna Rogelj, Alexander Kornienko, Liliya V. Frolova

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Plants of the Amaryllidaceae family produce a large variety of alkaloids and non-basic secondary metabolites, many of which are investigated for their promising anticancer activities. Of these, crinine-type alkaloids based on the 5,10b-ethanophenanthridine ring system were recently shown to be effective at inhibiting proliferation of cancer cells resistant to various pro-apoptotic stimuli and representing tumors with dismal prognoses refractory to current chemotherapy, such as glioma, melanoma, non-small-cell lung, esophageal, head and neck cancers, among others. Using this discovery as a starting point and taking advantage of a concise biomimetic route to the crinine skeleton, a collection of crinine analogues were synthetically prepared and evaluated against cancer cells. The compounds exhibited single-digit micromolar activities and retained this activity in a variety of drug-resistant cancer cell cultures. This investigation resulted in the discovery of new bicyclic ring systems with significant potential in the development of effective clinical cancer drugs capable of overcoming cancer chemotherapy resistance.

Original languageEnglish (US)
Pages (from-to)313-328
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume120
DOIs
StatePublished - Sep 14 2016

Keywords

  • Apoptosis resistance
  • Glioblastoma
  • Multidrug resistance
  • Translation inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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