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Table S1. Crystal data and structure refinement for HDp4mT. Identification code ds2369 Empirical formula C 13 H 13 N 5 S Formula weight 271.34 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 19.740(2) Å α= 90°. b = 11.694(1) Å β= 91.391(9)°. c = 11.514(2) Å γ = 90°. Volume 2657.1(6) Å 3 Z 8 Density (calculated) 1.357 Mg/m 3 Absorption coefficient 0.237 mm -1 F(000) 1136 Crystal size 0.5 x 0.5 x 0.3 mm 3 Theta range for data collection 2.02 to 24.96°. Index ranges 0<=h<=23, 0<=k<=13, -13<=l<=13 Reflections collected 2399 Independent reflections 2329 [R(int) = 0.0491] Completeness to theta = 24.96° 99.7 % Absorption correction Psi-scan Max. and min. transmission 0.9317 and 0.8896 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2329 / 0 / 172 Goodness-of-fit on F 2 1.039 Final R indices [I>2sigma(I)] R1 = 0.0382, wR2 = 0.0926 R indices (all data) R1 = 0.0623, wR2 = 0.1029 Largest diff. peak and hole 0.202 and -0.209 e.Å -3

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.

Serum albumin is a multi-functional protein that is able to bind and transport numerous endogenous and exogenous compounds. The development of albumin drug carriers is gaining increasing importance in the targeted delivery of cancer therapy, particularly as a result of the market approval of the paclitaxel-loaded albumin nanoparticle, Abraxane®. Considering this, there is renewed interest in isolating and characterizing albumin-binding proteins or receptors on the plasma membrane that are responsible for albumin uptake. Initially, the cellular uptake and intracellular localization of albumin was unknown due to the large confinement of the protein within the vascular and interstitial compartment of the body. Studies have since assessed the intracellular localization of albumin in order to understand the mechanisms and pathways responsible for its uptake, distribution and catabolism in multiple tissues, and this is reviewed herein.

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We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl](2), identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex.