Metallodrug-protein interactions

Since the discovery of platinum containing compounds in the treatment of a variety of cancers, remarkable progress has been made in understanding the 

The in vitro interactions of the cysteine-rich intracellular protein Zn7-metal-lothionein with cisplatin and transplatin and the histidine-rich proteins Hpni32,i33 HspA with a bismuth antiulcer compound were investigated, respectively. These kinds of interactions may play a crucial role in the metabolism of various metallodrugs. Notably, drug binding to plasma proteins has a strong influence on their biodistribution, biotransformation, and pharmacokinetics, and therefore merits further characterizations. 

Protein conformational changes induced by metallodrug binding could be studied by pulsed-field gradient diffusion NMR spectroscopy, circular dichroism (CD) or fluorescence spectra. Covalent binding of cisplatin to the Ca -binding protein calmodulin (CaM) was shown to induce a near complete collapse in the protein secondary structures, and resulted in a decrease of hydrodynamic radius to 21.4 0.2 A from 24.5 0.4 A for the 

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Casini A, Gabbiani C, Michelucci E, Pieraccini G, Moneti G, Dyson PJ, Messori L (2009) Exploring metallodrug-protein interactions by mass spectrometry comparisons between platinum coordination complexes and an organometallic ruthenium compound. J Biol Inorg Chem 14 761-770... 

Szpunar, J., Makarov, A., Lobinski, R., Pieper, T., Keppler, B. K. Investigation of metallodrug-protein interactions by size-exclusion chromatography coupled with inductively coupled plasma mass spectrometry (ICP-MS). Anal Chim Acta 1999, 387, 135-144. 

Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Interactions of antitumor metallodrugs with serum proteins advances in characterization using modem analytical methodology. Chem Rev 106 2224-2248... 

Albumin is one of the most abundant proteins in plasma ( 0.63 mM) and it is reasonable to assume that any injected metallodrug will present certain interactions with this macromolecule, which could largely determine its bioavailability and toxicology [42]. A comprehensive study of the reactions of the N-labeled cisplatin with intact and chemically modified recombinant human albumin (rHA) as well as human serum album (HSA) has been performed by ID H and [ H, Nj 2D HSQC NMR spectroscopy [53]. Recombinant albumin is similar to serum albumin but has a higher thiol content ( 0.9 -SH per rHA and only 0.4-SH per HSA) and is structurally more homogeneous. NMR studies showed that the major sulfur-containing binding site involves Met in the form of an S, N chelate but not Cys-34, which is commonly believed to be the major platination site of HSA (Scheme 5.4) [73]. 

With the exponential explosion of research into anticancer metallodrugs some original entities of Ru act via a structural role for the metal, which would give its shape to the compound and would favor noncovalent interactions with the target, as for example the organometallic 10 (Fig. 42.3), an excellent inhibitor of certain protein kinases developed by Meggers [27, 82],... 

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