RESUMEN
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.
Asunto(s)
Amidas/síntesis química , Amidas/toxicidad , Calcio/farmacología , Lactamas/química , Lactamas/toxicidad , Hidrocarburos Policíclicos Aromáticos/síntesis química , Hidrocarburos Policíclicos Aromáticos/toxicidad , Pirrolidinonas/química , Amidas/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclopentanos/química , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Estructura Molecular , Hidrocarburos Policíclicos Aromáticos/química , Relación Estructura-ActividadRESUMEN
Unnatural (-)-pectinatone ((-)-3) was prepared in five steps starting from the highly methyl-branched wax ester 4, employing bromination of the ester enolate and subsequent base-induced elimination to the enoate 6 as the key step. Both (-)-3 and the amides 8b and 8c, which were isolated as by-products in the reaction sequence, displayed antimicrobial activity and cytotoxicity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Ésteres/química , Pironas/síntesis química , Pironas/farmacología , Ceras/química , Animales , Antibacterianos/química , Productos Biológicos/farmacología , Línea Celular , Escherichia coli/efectos de los fármacos , Ratones , Micrococcus luteus/efectos de los fármacos , Estructura Molecular , Pironas/química , Staphylococcus aureus/efectos de los fármacosRESUMEN
OBJECTIVES: We aimed to investigate the contemporary usage rate and habits of the WHO Surgical Safety Checklist (SSC) in German urological departments. METHODS: We designed a 26-item questionnaire that was sent to all urological departments in Germany. The primary aim of this study was to evaluate the usage rate of the SSC. Secondary aims were to compare perioperative characteristics of users vs. non-users of the SSC and to assess circumstances of the SSC application. RESULTS: A total of 213 of 234 (91 %) urological departments were users of the SSC, and 21 (9 %) were non-users. SSC users had more often a standard protocol, took less time and had fewer people involved for checking perioperative patient data compared to non-users. Financial budgeting for the SSC existed in 55 (24 %) departments and for patient safety in 73 (32 %) departments. CONCLUSIONS: The usage rate of the SSC in urological departments in Germany is high despite restricted financial budgeting. Users of the SSC profit by saving time and manpower for checking perioperative patient data.