Cyanobacterial blooms have affected Lake Winnipeg since the mid-1990s due to an increased phosphorus loading into the lake, which has been exacerbated by stressors such as climate change and eutrophication. Aquatic ecosystems involving cyanobacteria have been found to contain N-β-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB), non-protein amino acids that are associated with neurodegenerative disease, as well as two of the naturally occurring isomers, N-2(amino)ethylglycine (AEG) and β-amino-N-methylalanine (BAMA). We hypothesized that the cyanobacterial bloom in Lake Winnipeg produces BMAA and/or its naturally occurring isomers. Samples of cyanobacteria were collected by the Lake Winnipeg Research Consortium from standard sampling stations and blooms in July and September of 2016 and were analyzed for BMAA, DAB, AEG, and BAMA using previously published validated analytical methods. BMAA and BAMA were found in the highest concentration in the center of the north basin, the deepest and lowest-nitrogen zone of the lake, at an average concentration of 4 μg/g (collected in July and September 2016) and 1.5 mg/g (collected in July 2016), respectively. AEG and DAB were found in the highest concentration in cyanobacterial blooms from the nearshore region of the north basin, the slightly shallower and more nitrogen-rich zone of the lake, at 2.1 mg/g (collected in July 2016) and 0.2 mg/g (collected in July and September 2016), respectively. These findings indicate that the production of non-protein amino acids varies with the depth and nutrient contents of the bloom. It is important to note that we did not measure food or water samples directly and further study of the Lake Winnipeg food web is required to determine whether BMAA bioaccumulation represents an increased risk factor for neurodegenerative disease in the region.
We report the total synthesis of the natural products isodihydrokoumine and (19 Z)-taberpsychine in 11 steps each and (4 R)-isodihydrokoumine N-oxide in 12 steps from commercially available starting materials. The key reactions include an intramolecular [3 + 2] nitrone cycloaddition and Lewis acid mediated cyclizations of a common intermediate to provide the core structures of either taberpsychine or isodihydrokoumine.
+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (-)-lysine via the intermediacy of the unstable cyclic imine Δ 1 -piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ 1 -piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, (+)-isomatrine is synthesized in four steps from inexpensive commercially available chemicals. (+)-Isomatrine then serves as the precursor to additional lupin alkaloids, including (+)-matrine, (+)allomatrine, (+)-isosophoridine, and (-)-sophoridine. Main text:The lupin alkaloids are a structurally diverse class of quinolizidine-containing natural products isolated from plants in the Lupinus genus (Fig. 1A). 1 (+)-Matrine (2), the primary component of Chinese Kushen injection, inhibits proliferation in metastatic cancer cell lines and has also been investigated as a therapeutic agent against encephalomyelitis, asthma, arthritis, and osteoporosis. 2,3 (-)-Sophoridine ( 4) is an approved chemotherapeutic in China, which has also demonstrated antibiotic activity. 4 Little is known about the pharmacological properties of (+)-isomatrine (1) and (+)-isosophoridine (5), which likely reflects their limited accessibility from commercial vendors. 5Although the detailed enzymatic pathway has not been fully annotated, the biosynthesis of matrine is proposed to initiate with the enzymatic conversion of (-)-lysine (6) to Δ 1 -piperidine (7) (Fig. 1B). 6,7 Subsequent dimerization of 7 followed by oxidation and isomerization is proposed to yield quinolizidine 8, a shared biosynthetic precursor to several lupin alkaloids. 8,9 Mannich addition of 8 to a third equivalent of 7 and cyclization
The C19 diterpenoid alkaloids (C19 DTAs) are a large family of natural products, many of which modulate the activity of ion channels in vivo and are therefore of interest for the study of neurological and cardiovascular diseases. The complex architectures of these molecules continue to challenge the state-of-the art in chemical synthesis, particularly with respect to efficient assembly of their polcyclic ring systems. Here, we report the total syntheses of (−)-talatisamine, (−)-liljestrandisine, and (−)-liljestrandinine, three aconitine-type C19 DTAs, using a fragment coupling strategy. Key to this approach is a 1,2-addition/semipinacol rearrangement sequence which efficiently joins two complex fragments and sets an all-carbon quaternary center.
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