Synthesis and biological properties of cylindramide derivatives: evidence for calcium-dependent cytotoxicity of tetramic acid lactams

To gain insight into the biol. properties of tetramic acid lactam cylindramide 1, the analogs 4a-d bearing a cyclopentane ring instead of the pentalene unit were prepd. by tandem conjugate addn./enolate trapping of cyclopentenone 10; a Sonogashira or Stille coupling, followed by a Julia-Kocienski olefination, macrolactamisation and Lacey-Dieckmann cyclisation were the key steps. The previous NMR structure of cylindramide 1, which was based on NOE and J coupling restraints, could be refined by including residual dipolar coupling data measured for a sample of cylindramide that was aligned in polyacrylonitrile (18%). Biol. screening of cylindramide 1 and its analogs 2-epi-1, 20 and 4 revealed promising antiproliferative activity against several tumor cell lines. It turned out that the activity is strongly correlated to the functionalised pentalene system. The configuration of the cyclopentane ring and an intact tetramic acid lactam with the correct configuration seem to play an equal role in the cytotoxicity. The antiproliferative activity was found to be calcium dependent. Phenotypic characterization of the mode of action showed vacuolisation and vesicle formation in the endoplasmic reticulum.