טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAlexander Shterenberg
SubjectConstruction of New Ligands for Peripheral-Type
Benzodiazepine Receptor (PBR)
DepartmentDepartment of Chemistry
Supervisors Full Professor Marek Ilan
Professor Emeritus Gavish Moshe


Abstract

Peripheral-type benzodiazepine receptor (PBR) is situated in the mitochondrial membrane. It is considered that PBR is a part of the mitochondrial permeability transition pore (MPTP).

The specific function of the PBR complex is still under debate. During our research we decided to concentrate on the involvement of PBR in apoptosis which is very important for multicellular organism: excess of apoptosis correlates with cell-loss disorders (Alzheimer's, Parkinson's), 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 PBR complex is part of MPTP, with the help of proper specific ligands to PBR, it may be possible to control the MPTP in the desired way: to induce the process of apoptosis or vice versa, to prevent it.

We are interested to attain a new class of specific PBR ligands, which would be more effective than those available, including strong anticancer or antiapoptotic effects in vitro and in vivo by selecting the various characteristics of the known PBR ligands and reassembling 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 PBR complex, according to formulated requirements for the structure of new ligands.

For this master thesis, we have prepared more than 30 new compounds from 4 different families: quinoxaline, quinazoline, phthalazine and dimers of PK 11195. Several parameters about the effect of various structural modifications on the biological activity have also been concluded. From all of these new compounds, some of them showed good binding to PBR and two ligands presented very good anti-apoptotic effect in vitro.

This initial research helped us to lay down the foundation for the design of new families of compounds and we are now hoping to find new leading molecules presenting good binding to PBR and excellent anti-apoptotic effects.