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Synthesis and Biological Properties of Cylindramide Derivatives: Evidence for Calcium‐Dependent Cytotoxicity of Tetramic Acid Lactams
Author(s) -
Cramer Nicolai,
Helbig Sarah,
Baro Angelika,
Laschat Sabine,
Diestel Randi,
Sasse Florenz,
Mathieu Daniel,
Richter Christian,
Kummerlöwe Grit,
Luy Burkhard,
Schwalbe Harald
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800284
Subject(s) - chemistry , stereochemistry , cytotoxicity , stille reaction , dihydropyran , biological activity , pharmacophore , biochemistry , in vitro , catalysis
To gain insight into the biological properties of tetramic acid lactam cylindramide 1 , the analogues 4 a – d bearing a cyclopentane ring instead of the pentalene unit were prepared by tandem conjugate addition/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 %). Biological screening of cylindramide 1 and its analogues 2‐epi‐ 1 , 20 and 4 revealed promising antiproliferative activity against several tumour 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 characterisation of the mode of action showed vacuolisation and vesicle formation in the endoplasmic reticulum.