Putative Intermediates in the Biosynthesis of Tedanolides
Final Report Abstract
We could establish the synthesis of des-epoxy-isotedanolide as the putative biosynthetic precursor of tedanolide. Des-epoxy-isotedanolide features basically the same acyclic skeleton as tedanolide, also the macrocyclic ring size remained the same. One could look at the difference between both compounds such that „only“ the side chain has been shifted from C17 to C29. Unfortunately we were not able to execute the transesterification under laboratory conditions. Biological investigations with des-epoxy-tedanolide and des-epoxy-isotedanolide showed that these compounds also inhibit the eukaryotic translation system as reported for tedanolide and related substances, but the inhibitory potential seen for des-epoxy-isotedanolide in vitro was weaker than expected from the anti-proliferative effect in cell culture. Detailed studies of the mode of action revealed that des-epoxy-tedanolide induces a phosphorylation of two factors in the initiation and the elongation part of the translation system, thereby effectively blocking the protein synthesis at two different sites. Whether this surprising result also holds true for des-epoxy-isotedanolide has to be investigated, yet. Our results are consistent with evolutionary optimization of the biological activity of the tedanolides, whether this is also connected with a change of targets has to be clarified.
Publications
- (2012) An improved route to (+)-tedanolide and analysis of its subtle effects controlling conformation and biological behaviour. Chemistry - A European Journal 18, 4946-4952
Diaz, N., Zhu, M., Ehrlich, G., Eggert, U., Muthukumar, Y., Sasse, F., Kalesse, M.
(See online at https://doi.org/10.1002/chem.201103038) - (2012) Synthesis of Simplified Tedanolide Analogues-Connecting Tedanolide to Myriaporone and Gephyronic Acid. ChemMedChem, 7, 771-775
Diaz, N., Naini, A., Muthukumar, Y., Sasse, F., Kalesse, M.
(See online at https://doi.org/10.1002/cmdc.201100576) - (2013) The marine polyketide myriaporone 3/4 stalls translation by targeting the elongation phase. ChemBioChem 14, 1439-7633
Muthukumar, Y., Roy, M., Raja, A., Taylor, R.E., Sasse, F.
(See online at https://doi.org/10.1002/cbic.201200522)
