Sidechain Diversification of Grandifloracin Allows Identification of Analogues with Enhanced Anti-Austerity Activity against Human PANC-1 Pancreatic Cancer Cells

© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. The natural product (+)-grandifloracin is a potent “anti-austerity” agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti-austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by-products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity.We thank EPSRC (DTP studentship to B.E.A.) and Cancer Research at Bath (CR@B) for funding. The biological investigation was supported by a grant from the Japanese Society for the Promotion of Science (JSPS Kakenhi #16 K08319) and the Kobayashi International Scholarship Foundation to S.A.Published versio

New Theonellapeptolides from Indonesian Marine Sponge Theonella swinhoei as Anti-Austerity Agents

We reported three new members of the theonellapeptolide family from theonellapeptolide II series, namely theonellapeptolides IIb (1), IIa (2), IIc (3), and three known members-IId (4), IIe (5), and Id (6)-from Kodingarengan marine sponge Theonella swinhoei collected in Makassar, Indonesia. The structures of tridecadepsipeptides 1-3, including the absolute configurations of their amino acids, were determined by the integrated NMR and tandem MS analyses followed by Marfey's analysis. To the best of our knowledge, 1 and 2 are the first theonellapeptolide-type compounds to have a valine residue with (D) configuration at residue position 6. The isolated theonellapeptolide-type compounds 1-6 showed selective cytotoxic activity against human pancreatic MIA PaCa-2 cancer cells in a nutrient-deprived medium. Among them, the most potent preferential cytotoxicity was observed in new theonellapeptolide IIc (3) and known IId (4), IIe (5), and Id (6)

A new polyoxygenated cyclohexane and other constituents from <i>Kaempferia rotunda</i> and their cytotoxic activity

<div><p>The isolation of secondary metabolites from a methanolic extract of <i>Kaempferia rotunda</i> yielded 12 compounds (<b>1</b>–<b>12</b>), including a new polyoxygenated cyclohexane compound, (–)-3-acetyl-4-benzoyl-1-benzoyloxymethyl-1,6-diepoxycyclohexan-2,3,4,5-tetrol (<b>1</b>). The structures of the isolated compounds were determined based on their spectroscopic data and comparison with references. All of the isolated compounds were tested for their cytotoxic activity against pancreatic (PSN-1) and breast (MDA-MB231) cancer cell lines. Compound <b>12</b> showed moderate cytotoxic activity against PSN-1 and MDA-MB231 without showing any cytotoxicity against the normal cell line, TIG-3.</p></div

Food-Derived beta-Carboline Alkaloids Ameliorate Lipid Droplet Accumulation in Human Hepatocytes

Lipid droplet accumulation (LDA) in hepatocytes is the initial stage of nonalcoholic fatty liver disease (NAFLD). In the search for natural compounds for the prevention of NAFLD, a series of beta-carboline alkaloid derivatives, inspired by flazin and its derivative, newly identified in Crassostrea gigas Thunberg. extracts, were examined for LDA inhibition (LDAI) activity in oleic acid-loaded hepatocytes (HepG2). Eight compounds with a piperidine or pyridine C-ring were chemically synthesized (1-8). Among them, compounds 2 and 4 (flazin) with a carboxy group at C-3 and furfuryl alcohol moiety at C-1 showed low cytotoxicity and they exhibited significant LDAI activity. Compound 2 with piperidine C-ring was identified for the first time in C. gigas extract, and ameliorated the lipid accumulation with the LDAI value of 25.4%. Active compounds 2 and 4 significantly inhibited triacylglycerol species accumulation in cells. These compounds upregulated ATGL and downregulated SREBP1, FASN, and SCD1 genes, suggesting that they activated lipolysis and suppressed lipogenesis, respectively. These results suggest that beta-carboline alkaloids, especially compounds 2 and 4, might be potentially useful for preventing NAFLD

Chemical Constituents of Thai <i>Citrus hystrix</i> and Their Antiausterity Activity against the PANC‑1 Human Pancreatic Cancer Cell Line

Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in a hypovascular tumor microenvironment. Searching for agents that preferentially inhibit cancer cell viability under nutrition starvation conditions is a novel antiausterity strategy in anticancer drug discovery. In the present study, a hexane extract of the peels of <i>Citrus hystrix</i> fruits showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells using a nutrient-deprived medium. Phytochemical investigation of this bioactive extract led to the isolation of 10 coumarins (<b>1</b>–<b>10</b>) including a new furanocoumarin (<b>1</b>). The isolated compounds were tested for their preferential cytotoxic activity against three different human pancreatic cancer cell lines [PANC-1, MIA PaCa-2, and PSN-1]. Among these, bergamottin (<b>7</b>) was identified as the most active constituent. In real-time live imaging, <b>7</b> was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (<b>7</b>) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, <b>7</b> inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (<b>7</b>) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer

Chemical Constituents of Thai <i>Citrus hystrix</i> and Their Antiausterity Activity against the PANC‑1 Human Pancreatic Cancer Cell Line

Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in a hypovascular tumor microenvironment. Searching for agents that preferentially inhibit cancer cell viability under nutrition starvation conditions is a novel antiausterity strategy in anticancer drug discovery. In the present study, a hexane extract of the peels of <i>Citrus hystrix</i> fruits showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells using a nutrient-deprived medium. Phytochemical investigation of this bioactive extract led to the isolation of 10 coumarins (<b>1</b>–<b>10</b>) including a new furanocoumarin (<b>1</b>). The isolated compounds were tested for their preferential cytotoxic activity against three different human pancreatic cancer cell lines [PANC-1, MIA PaCa-2, and PSN-1]. Among these, bergamottin (<b>7</b>) was identified as the most active constituent. In real-time live imaging, <b>7</b> was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (<b>7</b>) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, <b>7</b> inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (<b>7</b>) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer