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Beiträge zur Optimierung der Synthese und Entwicklung von Derivaten von (─)-Englerin A
| Content Provider | Semantic Scholar |
|---|---|
| Author | Hahn, Sven |
| Copyright Year | 2016 |
| Abstract | The guaiane sesquiterpene (─)-Englerin A has been reported to be a potent growth inhibitor for kidney-, renaland breast cancer cell lines, presumably by activation of TRPC4-ion channels and subsequent Ca-influx. In order to assure a reliable and efficient supply for further derivatisation, the synthetic route reported by Christmann et al. was significantly improved (chapter 3.1). 9] The sequence from alcohol 15 to olefin 18 required six steps with a total yield of 46% before the beginning of this work. By optimizations of the epimerization at C5 and the ring-closing metathesis two steps could be omitted increasing the yield to 83% over four steps. Though several SAR-studies to this lead-structure had been conducted, the inherent instability of the glycolate-moiety under physiological conditions had not been addressed previously. In order to overcome this problem, the ester-function was replaced by an amide and three aza-Englerin derivatives have been synthesized which show an increased stability, one of them 60 maintaining an acceptable (though lower) activity for TRCP4 (chapter 3.2). Another idea was to use a C-C-bond to fix the α-hydroxylcarbonyl attachment at C9 by a reductive alkylation strategy (chapter 3.3). The final hydrogenation yielded only the undesired epimer but was nevertheless transformed into the cinnamate 9-epi-61. Two intermediates on the way to 9-epi-61 were also transformed into the suitable derivatives for a biological evaluation (86 and 87). All synthesized carba-analoga were biologically inactive. Furthermore the modification of the isopropyl-substituent has been targeted. While the synthesis of a trifluoromethyl-derivative could not be completed due to problems with the ring-closing metathesis (chapter 3.5), a cyclopropyl-derivative 63 has been established (chapter 3.4). Its activity against TRPC4-channels is with an EC50 of 30.2 nM lower than (─)-Englerin A with an EC50 von 11.2 nM. Studies concerning its proliferative effect on the kidney cancer cell line A498 are ongoing. Overview over the biological activities of the derivatives for the Ca-influx in HEK-cells with overexpressed TRCP4-channels. |
| File Format | PDF HTM / HTML |
| DOI | 10.17169/refubium-17642 |
| Alternate Webpage(s) | https://refubium.fu-berlin.de/bitstream/handle/fub188/13444/Dissertation_Sven_Hahn.pdf?isAllowed=y&save=y&sequence=1 |
| Alternate Webpage(s) | https://doi.org/10.17169/refubium-17642 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
