Preparation of some semi-synthetic saponin analogs and investigation of their mechanism of action on necrotic cell death
tarafından
 
Üner, Göklem, author.

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
Üner, Göklem, author.

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.

Konu Başlığı
Cell death.
 
Necrosis.
 
Saponins.

Yazar Ek Girişi
Bedir, Erdal

Tüzel Kişi Ek Girişi
İzmir Institute of Technology. Biotechnology.

Tek Biçim Eser Adı
Thesis (Master)--İzmir Institute of Technology: Biotechnology.
 
İzmir Institute of Technology: Biotechnology--Thesis (Master).

Elektronik Erişim
Access to Electronic Versiyon.


LibraryMateryal TürüDemirbaş NumarasıYer NumarasıDurumu/İade Tarihi
IYTE LibraryTezT001958QH671 .U56 2019Tez Koleksiyonu