Restoration of apoptosis in cancer cells

Anti-apoptotic proteins Bcl-2 and Bcl-xL

Cancer is a broad group of diseases involving unregulated cell growth. Indeed, in cancer, cells divide and grow uncontrollably, forming malignant tumours, and invading nearby parts of the body. So far, chemotherapy - which induces a programmed cell death called apoptosis, and radiation - which directly kills the cells, are the main treatments for this disease. But for chemotherapy, one problem is that tumour cells often have high levels of active anti-apoptotic proteins, or proteins that prevent cell death. Among these are the anti-apoptotic proteins Bcl-2 and Bcl-xL which promote the survival of cancer cells. Some medicines already aim to inhibit those proteins, but in some cases, the treatment fails due to drug resistance properties of cancer cells.

Nowadays, scientists are looking for new techniques to trigger cell death or possibly overcome drug resistance.

Inhibition of Bcl-2 and Bcl-xL by incednine

In 2008, a new macrocyclic molecule called incednine, was discovered. It was isolated from a bacteria culture (Streptomyces sp.) and displayed anticancer activity. The mechanism has not yet been fully established but it appears that this molecule, combined with other anti-tumour agents, inhibits the mentioned overexpressed proteins (Bcl-2 and Bcl-xL), thus avoiding the survival of drug resistant cancer cells. Additional studies have shown that incednine does not inhibit Bcl-2 and Bcl-xL via the usual pathway of surface recognition of binding pockets. This new mechanism could be responsible for avoiding drug resistance. Thus, all those combined intriguing data and properties of incednine make this molecule an interesting target, which demands efficient ways for synthesis.

Aruncin B selectively induces apoptosis in cancer cells

Another hit has been isolated from the Korean plant Rosaceae (Aruncus dioicus var. kamtschaticus), found on the Island Ulleungdo, which is known for its antioxidant, antidiabetic and anti-AIDS properties. In 2011, the extraction of its aerial parts enabled the discovery of several new natural compounds, including Aruncin B, which has a unique chemical structure. This new natural product showed potential cytotoxicity (ability to kill cells) against the Jurkat T cell line (human cancer cell line commonly used to study T cell leukaemia). Further studies suggest that the cytotoxity of Aruncin B is due to the induction of phosphorylation (chemical modification of a protein) of the Bcl-2, which inactivates its anti-apoptotic activity. Moreover, it appears that Aruncin B is more cytotoxic in malignant cells than in normal human cells. The potential ability to selectively induce apoptosis in malignant cells makes Aruncin B a particularly interesting target for the development of novel anti-tumoural agents.

As natural molecules are usually present in small amounts in nature and as it is important to study all of the aspects of those new compounds, the overall project aims to synthesise those molecules including intermediates and analogues in order to study their biological properties. Those compounds will be accessed using both classic techniques in organic chemistry and new techniques, namely electrochemistry, biocatalysis and flow chemistry leading to higher sustainability.