Denhaminols A–H, Dihydro-β-agarofurans from the Endemic Australian Rainforest Plant <i>Denhamia celastroides</i>

Eight new dihydro-β-agarofurans, denhaminols A–H (<b>1</b>–<b>8</b>), were isolated from the leaves of the Australian rainforest tree <i>Denhamia celastroides</i>. The chemical structures of <b>1</b>–<b>8</b> were elucidated following analysis of 1D/2D NMR and MS data. The absolute configuration of denhaminol A (<b>1</b>) was determined by single-crystal X-ray crystallography. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP, using live-cell imaging and metabolic assays. Denhaminols A (<b>1</b>) and G (<b>7</b>) were also tested for their effects on the lipid content of LNCaP cells. This is the first report of secondary metabolites from <i>D. celastroides.</i

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Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells

The naturally occurring pentacyclic diterpenoid gibberellic acid (<b>1</b>) was used in the generation of a drug-like amide library using parallel-solution-phase synthesis. Prior to the synthesis, a virtual library was generated and prioritized based on drug-like physicochemical parameters such as log P, hydrogen bond donor/acceptor counts, and molecular weight. The structures of the synthesized analogues (<b>2</b>–<b>13</b>) were elucidated following analysis of the NMR, MS, UV, and IR data. Compound <b>12</b> afforded crystalline material, and its structure was confirmed by X-ray crystallographic analysis. All compounds were evaluated <i>in vitro</i> for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, synthesized analogues <b>3</b>, <b>5</b>, <b>7</b>, <b>10</b>, and <b>11</b> substantially reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism