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Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activityof the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control. Key words: C-1 homologues of pancratistatin, amaryllidaceae alkaloids, anticancer activities, intramolecular aziridine opening, solid-phase silica catalysis. On a realise la synthese de plusieurs homologues en C-1 de la pancratistatine et de la 7-desoxypencratistatine en faisant appel a une strategie de recyclisation oxydante phenantrene-phenathridone. Les etapes cles impliquent la dihydroxylation du bromobenzene, l'addition d'une arylalane a une epoxyaziridine, une ouverture intramoleculaire d'aziridine sur gel de silice en phase solide et la strategie de recyclisation mentionnee plus haut. Les donnees experimentales et spectrales sont rapportees pour tous les nouveaux produits. Tous les homologues en C-1 de la pancratistatine et de la 7-desoxypencratistatine ont ete e values pour leur activite a contrer la proliferation dans un eventail de lignees de cellules cancereuses humaines. Tel que prevu, les composes 7-hydroxy sont les plus puissants alors que l'activite de l'analogue C-1 benzoxymethyle est superieure a celle de la narciclasine qui a ete utilisee comme controle positif. Mots-cles : analogues en C-1 de la pancratistatine, alcaloides des amaryllidacees, activite anticancereuse, ouverture intramoleculaire d' aziridine, catalyse par le gel de silice en phase solide. [Traduit par la Redaction], Introduction Pancratistatin (1), narciclasine (2), and other Amaryllidaceae constituents, Fig. 1, continue to attract attention on account of their promising anticancer properties. Since the isolation of pancratistatin in 1984 by [...]

Experiments were performed to identify and clone a rat gene, DNase Y, encoding a 36 kDa endonuclease. Three overlapping genomic fragments consisting of an approximately 30 kb contig were isolated. A gene encoding a protein with high sequence similarity to a human DNase homologue was observed in the sequenced contig. Further analysis of the amino acid sequence revealed a typical eukaryotic signal peptide of amino acids including a charge N terminus, a hydrophobic core and a probable cleavage site, 'Ala-Leu-Ser.'

A novel 97 kDa Ca+2/Mg+2-dependent endonuclease was found to mediate apoptosis in cultured 5123tc rat hepatoma cells. The characterization of the enzyme revealed that its mechanism of action is by internucleosomal DNA cleavage which may be responsible for the secondary stages of chromatin degradation in apoptosis. It was also found to be active over a wide range of pH and inactivated by reducing agents. The identity of the new enzyme was confirmed different from known endonucleases such as DNases I and II based on its binding to rabbit polyclonal anti-p97 antibodies.

Abstract Background Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. Results Mononuclear cells from healthy volunteers and leukemia patients were exposed to 1 μM pancratistatin for up to 48 h. Irrespective of leukemia type, pancratistatin induced apoptosis in the leukemic samples, with minimal effects on non-cancerous peripheral blood mononuclear control cells. Conclusion Our results show that pancratistatin is an effective and selective anti-cancer agent with potential for advancement to clinical trials.

Abstract Background Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance. Results Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats. Conclusion Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.

Abstract Background Pancratistatin (PST), a compound extracted from an Amaryllidaceae (AMD) family plant, has been shown to specifically induce apoptosis in cancer cells with no/minimal toxic effect on normal cells. A systematic synthetic approach has indicated that the minimum cytotoxic pharmacophore comprises the trans-fused b/c-ring system containing the 2, 3, 4-triol unit in the C-ring. To further explore the structure-activity relationship of this group of compounds we have investigated the anti-cancer efficacy and specificity of two PST-related natural compounds, AMD4 and AMD5. Both of these compounds lack the polyhydroxylated lycorane element of PST instead having a methoxy-substuituted crinane skeleton. Results Our results indicate that AMD5 has efficacy and selectivity similar to PST, albeit at a 10-fold increased concentration. Interestingly AMD4 lacks apoptotic activity. Conclusion Our results indicate that the phenanthridone skeleton in natural Amaryllidaceae alkaloids may be a significant common element for selectivity against cancer cells; furthermore, the configuration of the methoxy-side groups is responsible for higher binding affinity to the target protein/s thus making for a more efficient anti-cancer agent.