DESIGN AND SYNTHESIS OF INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE-1 ENZYME BASED ON A PYRROLOBENZOXAZINE STRUCTURE

The poly(ADP-ribose)polymerase (PARP) enzymes are a family of proteins implicated in a number of key cellular processes including chromosome stability, regulation of apoptosis, cell division, and transcriptional regulation and differentiation. A particularly important role of PARPs is in the maintenance of DNA integrity as part of the base excision repair (BER) pathway to repair singlestrand breaks (SSBs) in DNA. PARP-1, one of the most abundant and well characterized members of the PARP family of nuclear enzymes, is over-expressed in a variety of cancers and thus represents a promising target in anticancer research. So far, several compounds, belonging to different chemical classes, have been identified as PARP-1 inhibitors confirming the great therapeutic potential of this target. Furthermore, such compounds seem able to enhance the anticancer efficacy of known cytotoxic chemotherapeutic agents. Earlier studies focusing on the discovery of PARP-1 inhibitors have led to the identification of a pharmacophore model consisting of a bicyclic amide core.The replacement of the amide with a bioisosteric lactone group together with the expansion to larger tri- or tetra-cyclic systems was then proposed, but not yet deeply explored.1 A series of variously substituted pyrrolo- and indolo-benzoxazine based compounds was designed in order to establish a coherent structure-activity relationship. The introduction of an additional electron-rich system, such as a pyrrole or an indole, on previously identified compounds should promote a better fitting with the enzymatic core. The synthesis of such derivatives was made possible by following original procedures recently developed in our laboratory (Scheme).2 Further chemical modifications and introduction of selected functional groups are currently under investigation in order to achieve analogs with improved enzymatic inhibitory efficacy.References 1Ferraris D.V. J. Med. Chem., 2010, 53, 12 4561–4584. 2Aiello F.; Garofalo A.; Grande F. Tetrahedron Lett., 2010, 51, 6635–6636.