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Increasing the bioavailability of Ru(III) anticancer complexes through hydrophobic albumin interactions.
- Source :
-
Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2013 Dec 09; Vol. 19 (50), pp. 17031-42. Date of Electronic Publication: 2013 Nov 07. - Publication Year :
- 2013
-
Abstract
- A series of pyridine-based derivatives of the clinically successful Ru(III)-based complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (KP1339) have been synthesized to probe the effect of hydrophobic interactions with human serum albumin (hsA) on anticancer activity. The solution behavior and protein interactions of the new compounds were characterized by using electron paramagnetic resonance (EPR) and UV/Vis spectroscopy. These studies have revealed that incorporation of hydrophobic substituents at the 4'-position of the axial pyridine ligand stabilizes non-coordinate interactions with hsA. As a consequence, direct coordination to the protein is inhibited, which is expected to increase the bioavailability of the complexes, thus potentially leading to improved anticancer activity. By using this approach, the lifetimes of hydrophobic protein interactions were extended from 2 h for the unsubstituted pyridine complex, to more than 24 h for several derivatives. Free complexes were tested for their anticancer activity against the SW480 human colon carcinoma cell line, exhibiting low cytotoxicity. Pre-treatment with hsA improved the solubility of every compound and led to some changes in activity. Particularly notable was the difference in activity between the methyl- and dibenzyl-functionalized complexes. The former shows reduced activity after incubation with hsA, indicating reduced bioavailability due to protein coordination. The latter exhibits little activity on its own but, following treatment with hsA, exhibited significant cytotoxicity, which is consistent with its ability to form non-coordinate interactions with the protein. Overall, our studies demonstrate that non-coordinate interactions with hsA are a viable target for enhancing the activity of Ru(III)-based complexes in vivo.<br /> (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Cell Line, Tumor
Cell Proliferation
Crystallography, X-Ray
Electron Spin Resonance Spectroscopy
Humans
Hydrophobic and Hydrophilic Interactions
Ligands
Molecular Structure
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Colonic Neoplasms chemistry
Colonic Neoplasms drug therapy
Indazoles chemistry
Indazoles pharmacology
Organometallic Compounds chemistry
Organometallic Compounds pharmacology
Ruthenium chemistry
Ruthenium Compounds chemistry
Ruthenium Compounds pharmacology
Serum Albumin chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3765
- Volume :
- 19
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- Chemistry (Weinheim an der Bergstrasse, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 24203647
- Full Text :
- https://doi.org/10.1002/chem.201302671