Development of PARP-1 inhibitors as novel anticancer drugs

Despite the considerable advances in technology and anticancer chemotherapy, there is still need to develop highly active, well-tolerated, and ideally orally active drugs, which exploit the increased understanding of tumor biology. Due to the similarity of healthy cells with cancer cells the effectiveness of many available anticancer drugs is limited by their toxicity to normal cells and the rapid emergence of drug resistant. Consequently, there is a significant interest to develop novel agents selectively targeting specific enzymes or cell cycle processes in unhealthy cells. Recently, anticancer research has focused on development of compounds targeting physiological enzymes, that modulate a wide variety of cellular functions, including cell differentiation, cell cycle progression, apoptosis and angiogenesis. Nowadays, the Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) represents one of the most promising target in anticancer research. PARP-1 facilitates DNA single-strand break–base excision repair to maintain genomic stability. Often referred to as the “guardian angel of DNA”, this nuclear enzyme seems involved in a wide range of diseases such as cardiac disorders, cancer, inflammation and diabetes. Several studies have focused on the discovery of small molecules able to inhibit such enzyme leading to the identification of a pharmacophore model (Figure 1A).1 The cyclic amide moiety was described to be essential for activity, even though its replacement with a bioisosteric lactone group was not yet explored. Accordingly, several compounds have been synthesized in order to establish a coherent mode of action and structure-activity relationship following synthetic procedures recently performed by our research group.2 In particular, in this study we have focused on the design and synthesis of two series of variously substituted pyrrolobenzoxazine based compounds endowed with the essential structural requirements for anti-enzymatic activity (Figure 1B). Preliminary biological assays are now undergoing in order to evaluate their cytotoxic properties and enzymatic inhibition capability.