Ribisins and Certain Analogues Exert Neuroprotective Effects through Activation of the Keap1-Nrf2-ARE Pathway.

Oxidative stress contributes to the pathogenesis of various neurodegenerative diseases and induction of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a validated neuroprotective strategy. Synthetically-derived samples of members of the ribisin class of natural product together with a range of analogues were evaluated for their neuroprotective capacities. Four of the twenty-four compounds tested were found to strongly stimulate antioxidant response element-dependent transcriptional activity in human-derived SH-SY5Y cells. Further, in rat pheochromocytoma PC12 cells and mouse brain cortical cultures these compounds upregulated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene products, namely heme oxygenase (HO-1) and NAD(P)H quinone reductase 1 (NQO1). Functionally speaking, the compounds conferred protection in these cell models challenged with H2 O2 . In silico molecular modeling suggests that certain of the ribisins can dock in the Nrf2-binding Kelch domain in Keap1, while cysteine labeling by biotinylated iodoacetamide suggest that cysteine residues within Keap1 react with the ribisins. It is thus proposed that the most active compounds exert their neuroprotective activities by targeting Keap1, thereby activating Nrf2 and so increasing transactivation of Nrf2-responsive genes that encode for detoxifying and antioxidant enzymes.

A Formal Total Synthesis of (±)-Kopsihainanine A Using a Raney-Cobalt Mediated Reductive Cyclization Route to Polyhydroquinolines.

Perhydroquinoline 4, the product of a Raney-cobalt mediated reductive cyclization reaction, was readily converted into the cis-ring-fused perhydroquinoline 15 that could be epimerized to its trans-fused counterpart 2 on sequential treatment with iodosylbenzene then sodium borohydride. Tetracycle 2 is an advanced intermediate associated with a recently reported total synthesis of the alkaloid kopsihainanine A (1).

RANEY® cobalt--an underutilised reagent for the selective cleavage of C-X and N-O bonds.

RANEY® cobalt, which was first prepared in the 1930s, is known to function effectively as a catalyst for certain chemoselective reductions. However, its utility in chemical synthesis does not seem to have been fully appreciated. This first comprehensive survey of the literature on chemical transformations involving RANEY® cobalt attempts to redress matters by, among other things, highlighting the differences between the performance of this system and its much more well-known but usually less selective congener RANEY® nickel. A reliable method for preparing consistently effective RANEY® cobalt is presented together with a protocol that avoids the need to use it with high pressures of dihydrogen. As such, it is hoped more attention will now be accorded to the title reagent that offers considerable promise as a powerful tool for chemical synthesis, particularly in the assembly of polycyclic frameworks through tandem reductive cyclisation processes.

Discovery and evaluation of thiazinoquinones as anti-protozoal agents.

Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 µM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 µM) while exhibiting low levels of cytotoxicity (L6, IC50 167 µM). A series of C-7 amide and Δ²(³) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62-6.5 µM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ²(³)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ²(³)-phenethylamide 8e (IC50 0.67 µM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34-0.035 µM) combined with excellent selectivity (SI 560-4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively.

Application of a Raney-cobalt-mediated tandem reductive cyclization protocol to total syntheses of the Aspidosperma alkaloids (±)-limaspermidine and (±)-1-acetylaspidoalbidine.

The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raney-cobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (±)-1 has been converted over two steps into (±)-1-acetylaspidoalbidine [(±)-13].