European Journal of Medicinal Chemistry: 5,10b-Ethanophenanthridine amaryllidaceae alkaloids inspire the discovery of novel bicyclic ring systems with activity against drug resistant cancer cells
Author links open overlay panelAuthor links open overlay panelSean Henrya\, Ria Kidnera, Mary R.Reisenauera, Igor V .Magedova, Robert Kissb, Véronique Mathieub, Florence Lefrancc, Ramesh Dasarid, Antonio Evidentee, Xiaojie Yuf, Xiuye Maf, Alexander Pertsemlidisf, Regina Cencicg, Jerry Pelletierg, David A.Cavazosh, Andrew J.Brennerh, Alexander V.Aksenovi, SneznaRogelja, Liliya V.Frolovaa
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.
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