Design, Synthesis, and Characterization of Novel Iron Chelators:  Structure−Activity Relationships of the 2-Benzoylpyridine Thiosemicarbazone Series and Their 3-Nitrobenzoyl Analogues as Potent Antitumor Agents

Abstract

Previously, we demonstrated that the potent antiproliferative activity of the di-2-pyridylketone thiosemicarbazone (DpT) series of Fe chelators was due to their ability to induce Fe depletion and form redox-active Fe complexes (Richardson, D. R.; et al. J. Med. Chem. 2006, 49, 6510-6521). We now examine the role of aromatic substituents on the antiproliferative and redox activity of novel DpT analogues, namely, the 2-benzoylpyridine thiosemicarbazone (BpT) and 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (NBpT) series. Both series exhibited selective antiproliferative effects, with the majority having greater antineoplastic activity than their DpT homologues. This makes the BpT chelators the most active anticancer agents developed within our laboratory. The BpT series Fe complexes exhibit lower redox potentials than their corresponding DpT and NBpT complexes, highlighting their enhanced redox activity. The increased ability of BpT-Fe complexes to catalyze ascorbate oxidation and benzoate hydroxylation, relative to their DpT and NBpT analogues, suggested that redox cycling plays an important role in their antiproliferative activity.

Tuning Cell Cycle Regulation with an Iron Key

“…Among these ligands are 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine ® ), 74 Tachpyridine, 75 O-Trensox 76 and hybrid chelators derived from pyridoxal isonicotinoyl hydrazone (PIH) 77,78 and thiosemicarbazones. [79][80][81][82][83][84] The success of Fe chelators as potential anti-tumor agents is marked by the entry of Triapine ® into phase I and II clinical trials alone or in combination with a range of chemotherapeutics. 85,86 In fact, recent results with this agent have shown that it can successfully reduce white blood cell counts by 50% in leukemia patients.…”

“…72,90,91 Studies with 311 and its derivatives 83,92 led to the development of a highly potent series of Fe chelators derived from di-2-pyridylketone thiosemicarbazone (DpT). 59,84,93,94 A number of these ligands have also demonstrated marked in vitro and in vivo anti-tumor activity 82,84,93,94 and are currently being developed as novel anti-cancer agents.…”

A novel mTOR inhibitor is efficacious in a murine model of colitis

“…Prior studies have shown that pyridine-based molecules are known to possess antiproliferative properties (20,22,30). mTOR is a protein kinase that regulates cell proliferation (18,40).…”

“…The pyridine scaffold is a very common structural motif that can be found in many natural products and in several pharmacologically interesting compounds (20,22,30). Therefore, the synthesis of pyridine derivatives, with the objective of devel-oping new drugs, is an active area of research.…”

Cellular Uptake of the Antitumor Agent Dp44mT Occurs via a Carrier/Receptor-Mediated Mechanism

“…The synthesis and characterization of these compounds have been described in detail in previous publications (Yuan et al, 2004;Richardson et al, 2006;Kalinowski et al, 2007;Jansson et al, 2010) and include:…”