Synthesis and biological properties of cylindramide derivatives: evidence for calcium-dependent cytotoxicity of tetramic acid lactams.
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.
Cramer
Nicolai
N
Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
Helbig
Sarah
S
Baro
Angelika
A
Laschat
Sabine
S
Diestel
Randi
R
Sasse
Florenz
F
Mathieu
Daniel
D
Richter
Christian
C
Kummerlöwe
Grit
G
Luy
Burkhard
B
Schwalbe
Harald
H
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000737:chemistry; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000633:toxicity*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D011760:Pyrrolidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000577:Amides; D003517:Cyclopentanes; D007769:Lactams; D011084:Polycyclic Aromatic Hydrocarbons; D011760:Pyrrolidinones; C511469:cylindramide; C009435:tetramic acid; D002118:Calcium