Synthesis and biological evaluation of new PAC-1 derivatives

Abstract

Cancer is one of the leading causes of death in the world. In developing countries cancer is claiming more lives than HIV & AIDS, tuberculosis and malaria combined. Cancer is generally known to be a disease with uncontrolled multiplication; in other words, cells reproduce in defiance of normal restraints on cell division. It is also known to invade and colonize territories far from the infection area.

As the science of cancer is developing, researchers are seeing light at the end of the tunnel. Cancer is known to be a disease of genetic disorders, though it is much more than that with hallmarks like evading apoptosis. Most of the chemotherapeutic drugs activate apoptosis by using p53 pathway. Unfortunately, in most of the cancer cases p53 is mutated; therefore efforts were made to bypass this mutation since it happens upstream and make molecules that target further downstream in the signal pathway.

It is the aim of this thesis to shed more light on the possibility of targeting not only downstream targets in the apoptosis cascade, but the main executioner which is caspase-3. The idea was to make more potent derivatives of PAC-1, which can lead to cell death and hopefully new leads for cancer drugs. A total of five compounds were synthesized including PAC-1 as a positive control. The compounds were characterised with the help of 1H NMR, 13C NMR and LC-MS. They were later subjected to biological testing whereby PC-12 cells were treated with the compounds. After 48 hours of incubation the cell viability was measured. It was found that all the compounds had an effect in reducing cell viability.