Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells

Abstract

In a search of small molecules active against apoptosis-resistant cancer cells, a skeletal rearrangement of alkaloid haemanthamine was utilized to generate a series of compounds possessing the alkaloid montanine ring system. The synthesized compounds were found to inhibit proliferation of cancer cells resistant to apoptosis at micromolar concentrations. Selected compounds were also active against patient-derived glioblastoma cells expressing stem-cell markers. This is the first report describing the preparation of synthetic analogues of the montanine-type alkaloids with antiproliferative activity. The compounds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with poor prognoses.

Amaryllidaceae Alkaloids of Different Structural Types from Narcissus L. cv. Professor Einstein and Their Cytotoxic Activity

“…Although previous studies, as well as our work, have demonstrated that AA of the montanine type can effectively suppress viability and proliferation of human cancer cells, the molecular mechanism of this cytotoxic activity has not yet been fully explored and is still waiting to be described. Montanine and manthine showed strong in vitro growth inhibitory effect on three apoptosis-resistant cancer cell lines (A549, SKMEL-29, and U373) and three apoptosis-sensitive cancer cell lines (MCF7, Hs683, and B16F10) with IC 50 values between 5 and 31 µM [12]. In another recent study, C-2α-/C-2β-methoxy isomers montanine and coccinine were found to significantly affect the proliferation of human breast, colon, lung, and melanoma cancer cell lines over 48 h of treatment.…”

“…Professor Einstein resulted in the isolation of 23 known AA , and a new alkaloid (24). The compounds were analyzed by various spectroscopic methods (GC-MS, LC-MS, and 1D and 2D NMR spectroscopy) and identified by comparison with literature data as masonine (1) [22], homolycorine (2) [23], ismine (3) [24], caranine (4) [25], galanthamine (5) [26], narwedine (6) [27], lycoraminone (7) [28], pluviine (8) [25], incartine (9) [29], galanthine (10) [30], lycoramine (11) [26], epinorgalanthamine (12) [31], norlycoramine (13) [32], haemanthamine (14) [32], hippeastrine (15) [33], epimaritidine (16) [34], lycorine (17) [35], tazettine (18) [36], eugenine (19) [37], norpluviine (20) [38], 9-O-demethylmaritidine (21) [39], pancracine (22) [40], and 9-O-demethylhomolycorine (23) [23] (Figure 1). The alkaloids that were isolated were representatives of the homolycorine (1,2,15,19,23), galanthamine (5,6,…”

“…They are characterized by a 5,11-methanomorphantridine ring system, the only differencies being the substitutions and configuration at C-2 and C-3 centers (Figure 3) [40]. Some of these compounds have been screened against different cancerous cells [12,41]. Montanine and manthine showed strong in vitro growth inhibitory effect on three apoptosisresistant cancer cell lines (A549, SKMEL-29, and U373) and three apoptosis-sensitive cancer cell lines (MCF7, Hs683, and B16F10) with IC50 values between 5 and 31 µM [12].…”

“…Some of these compounds have been screened against different cancerous cells [12,41]. Montanine and manthine showed strong in vitro growth inhibitory effect on three apoptosisresistant cancer cell lines (A549, SKMEL-29, and U373) and three apoptosis-sensitive cancer cell lines (MCF7, Hs683, and B16F10) with IC50 values between 5 and 31 µM [12]. In another recent study, C-2α-/C-2β-methoxy isomers montanine and coccinine were found to significantly affect the proliferation of human breast, colon, lung, and melanoma cancer cell lines over 48 h of treatment.…”

“…Numerous products of natural origin are known for their cytotoxic activity. These products are also a source of substances capable of affecting apoptosis resistance [12]. Simultaneously, the anti-invasive and anti-metastatic effects of some plant alkaloids have been described [13,14].…”