Design Synthesis And Biological Activity Of Novel Molecules Designed To Target Parp And Dna

"According to the most recent Canadian statistics, the expected likelihood of women developing either breast or ovarian cancer throughout their lifetime is 26.1% and 2.9% respectively. Furthermore, breast cancer in women is the most prominent in the list of expected cancer development and its percentage is approximately twofold that of second place: lung cancer. Common to both men and women, pancreatic cancer has a 2.4% and 2.5% incidence of development respectively. In the previous decade, a commonality in these cancers has been discovered. in that a mutation in DNA repair proteins known as BRCA1 and 2 renders these gene products non-functional. A DNA repair protein, known as poly (ADP-Ribose) polymerase (PARP), then becomes the only means by which mutated cells with defective BRCA gene products can repair DNA. As a result, if PARP is inhibited within mutated cells with defective BRCA gene products, they become incapable of repairing DNA lesions and ultimately undergo cell death. This translated into a novel strategy for the selective therapy of tumours with cancer susceptibility gene termed "synthetic lethality". Despite the successful proof-of-concept for synthetic lethality in the clinic, acquired resistance have been reported. In order to enhance the potency of the approach, we sought to synthesize PARP inhibitors capable of not only blocking PARP function but also alkylating DNA. Thus, we identified EG40, a PARP inhibitor carrying a chloroethyltriazolinium moiety. Using the sulphorhodamine B (SRB) assays, we showed that EG40 is 2.5-fold more potent than its PARP inhibitor counterpart, PARP-4-ANI, and displays 25-fold selectivity for the BRCA2 mutant in an isogenic pair of cell lines. We assessed the binary targeting ability of EG40 using the comet assay to measure the extent of DNA damage, as well as using a PARP assay to measure the extent of PARP inhibition. EG40 inhibits PARP 20-fold more weakly when compared to the naked PARP-4-ANI scaffold and induces significant DNA damage against VC8 mutant cells. In conclusion, we have developed a drug that acts more effectively in terms of potency while maintaining selectivity for its counterpart. Furthermore this drug is effective in inhibiting PARP and causing DNA damage. This gives prima facie evidence that a single molecule termed combi-molecule with dual PARP-DNA targeting function can be highly effective in tumors containing BRCA1 or 2 mutations." --