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Preparation of some semi-synthetic saponin analogs and investigation of their mechanism of action on necrotic cell death için kapak resmi
Preparation of some semi-synthetic saponin analogs and investigation of their mechanism of action on necrotic cell death
Başlık:
Preparation of some semi-synthetic saponin analogs and investigation of their mechanism of action on necrotic cell death
Yazar:
Üner, Göklem, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
xvi, 152 leaves: charts;+ 1 computer laser optical disc.
Özet:
Since antitumor potency of saponins is relatively weak, researchers focus on semi-synthetic modification of saponins to obtain highly potent structures. With the same motivation, we prepared cytotoxic sapogenol (AG-08), from cycloastragenol. Our preliminary studies revealed that AG-08 was inducing necrotic cell death together with autophagic inhibition. Furthermore, immunoblotting experiments suggested that AG-08 promoted cleavage of various proteins. A continuation study was performed in this thesis with aims of: i) verifying previous studies; ii) identifying molecular mechanism of AG-08; iii) preparing further analogs of AG-08 and deduce structure activity relationships(SAR). Accordingly, necrotic cell death and autophagic inhibition via AG-08 was verified, and cytotoxicity of AG-08 on 13 cell lines was examined. Furthermore, inhibitors of calpain-1, general caspases, cathepsin B/L/S, and caspase-8 were found to partially alleviate cell death, whereas cathepsin D/E inhibitor were not able to do. Additionally, lysosomal impairment due to loss of acidic nature was demonstrated. Later data and effect of cathepsin inhibitor on AG-08 mediated cell death suggest lysosomal membrane permeabilization. In synthesis part, 15 AG-08 analogs were prepared, three of which were cytotoxic. Additionally, active analogs triggered similar cell death mechanism with AG-08. SAR evaluation reveals that presence of tosyl, and tetrahydrofuran ring are required for activity, while double bond at C-6 is not essential. Consequently, this thesis provides important data on mechanism of necrotic cell death and autophagic inhibition via AG-08 treatment as well as relationship between structure and activity. However, further studies are warranted to clarify complete mechanism of AG-08 and substantiate structure activity relationship deductions.
Yazar Ek Girişi:
Tek Biçim Eser Adı:
Thesis (Master)--İzmir Institute of Technology: Biotechnology.

İzmir Institute of Technology: Biotechnology--Thesis (Master).
Elektronik Erişim:
Access to Electronic Versiyon.
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