Isolation and total synthesis of gymnastatin N, a POLO-like kinase 1 active constituent from the fungus Arachniotus punctatus

A high throughput screen against POLO-like kinase I (Plk1), an anti-cancer target, identified an active extract from the fungus Arachniotus punctatus. Bioassay guided fractionation led to the isolation of the new natural product, gymnastatin N (1) and the known compound aranorosinol A (2) with IC50 values of 13 and H 8 muM, respectively. A 12'-hydroxy analog of gymnastatin N, 3, was also isolated as a minor component. Gymnastatin N (1) was found to be a 52:48 mixture of (I S,6'R) and (I R,6'R) diastereomers, by synthesis of the four possible diastereomers and comparison of the optical rotation and chiral HPLC profile of each diastereoisomer with the natural product. Analogues of I were synthesized and evaluated against the Plk1 assay and these SAR studies suggested that the diene and free carboxylic acid moieties might be responsible for its bioactivity. (C) 2004 Elsevier Ltd. All fights reserved.