Hydrazide-based inhibitors of HDAC enzymes as novel anticancer drugs

Cancer is a word widely used to indicate a class of diseases characterized by uncontrolled cells division. Nowadays it is responsible for about 25% of all deaths in the developed countries. 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, often over-expressed in cancer cells, that modulate a wide variety of cellular functions, including cell differentiation, cell cycle progression, apoptosis, cytoskeletal modifications, and angiogenesis. Histone deacetylases (HDACs) inhibitors represent one of the most promising class of antitumoral agents, since HDAC catalyze the acetylation of histones, the building blocks of chromatin. Histones acetylation is a post-translational modification directly involved with the regulation of gene expression in eukaryotes.1,2 Thus, in relation to the aberrant gene expression often observed in cancer, HDAC has recently become a major focus of attention as a new target for the development of novel anticancer drugs.The overall goals of this study have been the design, synthesis and biological evaluation of small molecules potentially active as HDAC inhibitors. A new class of (pyrazinecarbo) hydrazides (I) with anticancer activity has been identified by testing against HDAC and a series of structurally related compounds has been prepared, in order to establish a coherent mode of action and structure-activity relationship. Their peculiar structural feature is the presence of a hydrazide moiety linking a nitrogen containing aromatic system to the pyrazine. In particular, a substituted quinoxaline or a tricyclic pyrroloquinoxaline system resulted as a critical structural requirement for anti-enzymatic activity. These compounds have been further evaluated in in vitro and in vivo assays against a range of human tumor cell type and some of them showed remarkable activity, confirming their potential application in clinical experimentation. Further studies are in progress with the aim to develop a more comprehensive structure–activity relationship amongst these novel compounds and understand the mechanisms involved in their HDAC inhibitory activity.