טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentTsoglin Einav
SubjectConstruction of New TSPO Ligands with Anti Cancer or
Neuroprotective Effects and Diastereoselective
Synthesis of Cyclobutyl Zirconocene
Derivative
DepartmentDepartment of Chemistry
Supervisors Professor Ilan Marek
Professor Emeritus Moshe Gavish
Full Thesis textFull thesis text - English Version


Abstract

The first part of the master thesis deals with the 18kDa Translocator Protein (TSPO). It is situated in the outer mitochondrial membrane and is considered to be a part of the mitochondrial permeability transition pore (MPTP). The specific function of TSPO complex is still under debate. Current research concentrates on the involvement of TSPO in apoptosis which is very important for multicellular organisms: excess of apoptosis correlates with cell-loss disorders, whereas reduced apoptotic rates correlate with cancer. The intrinsic pathway of apoptosis passes through the mitochondria. The key step in this pathway is the release of cytochrome C from the mitochondria. An increased Ca2+ concentration inside the cytosol may lead to the activation of the intrinsic apoptotic pathway via opening of the MPTP. Since the TSPO is closely associated to the MPTP, it may be possible to control the MPTP in the desired way, with the help of proper specific ligands to TSPO: to induce the process of apoptosis or vice versa, to prevent it. We are interested to obtain a new class of specific TSPO ligands, which would be more effective than those available, including strong pro-apoptotic or anti-apoptotic effects in vitro and in vivo by selecting the various characteristics of the known TSPO ligands and incorporating them into new molecules. The design of new compounds was directed at simplifying the molecular structure for purposes of gaining more facile access to the TSPO complex, according to formulated requirements for the structure of new ligands. For this master thesis, more than 20 new compounds from quinazoline family and dimers of PK 11195 were prepared. Several parameters about the effect of various structural modifications on the biological activity have also been deduced. Several compounds showed good binding to TSPO. Two ligands presented anti-apoptotic effect in vitro and two other ligands presented pro-apoptotic effect in vitro. This research helped us to lay down the foundation for the design of new families of compounds. The second part of this thesis is related to the diastereoselective synthesis of cyclobutyl zirconocene derivatives using Cp2ZrEt2. The zirconation reaction was performed from pure Z-vinyl carbamate. A new intramolecular cyclization reaction was observed that leads to the formation of metallated cyclobutane. The cyclobutyl zirconocene was trapped by different electrophiles to give the disubstituted cyclobutane derivative as a single diastereoisomer.