hamayne and crinine

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.

Topics: Amaryllidaceae; Amaryllidaceae Alkaloids; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Plant Extracts; Tumor Cells, Cultured

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.

Topics: Amaryllidaceae Alkaloids; Antineoplastic Agents, Phytogenic; Computer Simulation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Molecular Structure; Plant Roots

The racemic form of the title alkaloid, 1, has been prepared in 13 steps from the ring-fused gem-dibromocyclopropane 7. Key transformations include the thermally induced electrocyclic ring-opening of compound 7, the Pd[0]-catalyzed intramolecular Alder-ene (IMAE) reaction of the derived sulfonamide (±)-12, and the conversion of the ensuing C-3a-arylhexahydroindole (±)-16 into (±)-hamayne via a Pictet-Spengler reaction.

Topics: Amaryllidaceae Alkaloids; Catalysis; Models, Molecular; Molecular Structure; Palladium; Stereoisomerism