Design, Synthesis, and Anticancer Activity of Novel Pyridyl and Aryl Hydrazones

Cancer is continuing to be a major health issue and despite the recent improvements in the chemotherapeutic management of some type of cancers, the therapeutic effectiveness toward the majority of solid tumors is relatively low. Half of all cancer patients fail to respond to chemotherapy and ultimately die for the disease progression. Recently, combination chemotherapy has improved dramatically the clinical outcomes of cancer patients. Even so, current treatments often do not completely release patients of their cancers and cancer cells can become resistant to various anticancer agents. Thus, the continued commitment to the arduous task of discovering new antineoplastic therapeutic agents remains critically important. The pronounced antineoplastic efficacy of hydrazones has been widely attributed to their inhibition of the mammalian enzyme Ribonucleotide Reductase (RNR), a key enzyme in DNA synthesis and cell growth control [1]. The enzyme is composed of a complex of two subunits, named R1 and R2. The R1 subunit contains the active site, while the R2 subunit contains a diferric-tyrosyl radical cofactor. Potent inhibitors interfering with the R2 subunit include the R-(N)-heterocyclic carboxaldehyde thiosemicarbazones (TSCs, such as Triapine) and the 2-acylpyridine-R-(N)-hetarylhydrazones. Currently, Triapine is in phase II clinical trial for cancer treatment, even though causes neutropenia, hypoxia and methaemoglobinemia. Following these observations, a range of chelators have been developed with improved iron chelation efficacy, lipophilicity and anti-cancer activity. Among these ligands are those of the hydrazone and thiosemicarbazone classes that demonstrate better efficacy than Triapine (e.g. Desforrioxamine, DFO or 2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, Dp44mT). From SAR studies of these compounds, it has been deducted that an N*-N*-S* or N*-N*-N* structural motif is essential for RNR inhibition [2]. As a logical continuation, we have synthesized a series of pyridyl and aryl hydrazones as potential RNR inhibitors. In addition, compounds containing a carbon-nitrogen C=N double bond (e.g. hydrazones, acyl hydrazones) present the very attractive feature of being double dynamic entities capable of undergoing both configurational and constitutional changes, as well as metal-ion coordination. The configuration of these compounds has been assigned according to the literature and was established to be E by means of 2D-1H-NMR spectroscopy. The antiproliferative activity of the novel pyridyl and aryl hydazones against a panel of human tumor cell lines will be presented. 1. Aye, Y.; Li, M.; Long, M.J.; Weiss, R.S. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene, 2014, 6, 155-163. 2. Shao J, Liu X, Zhu L, Yen Y Targeting ribonucleotide reductase for cancer therapy. Expert Opin Ther Targets. 2013, 12, 1423-1437.