Conjugation of organoruthenium(II) 3-(1H-benzimidazol-2-yl)pyrazolo[3,4-b]pyridines and indolo[3,2-d]benzazepines to recombinant human serum albumin: a strategy to enhance cytotoxicity in cancer cells.

Abstract

Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (1c-5c) of the general formula [RuCl(η(6)-arene)(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η(6)-benzylamide and L is a Cdk inhibitor [3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) and indolo[3,2-d]benzazepines (L4 and L5)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2-3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of 1c and 2c(-HCl) afforded residues, which after recrystallization from EtOH and EtOH/H(2)O, respectively, were shown by X-ray diffraction to be cis,cis-[Ru(II)Cl(2)(DMSO)(2)(L1)]·H(2)O and mer-[Ru(II)Cl(DMSO)(3)(L2-H)]·H(2)O. Compound 5c, with a coordinated amidine unit, undergoes E/Z isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes 1c-5c are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, 1c-5c were conjugated to recombinant human serum albumin, potentially exploiting the so-called "enhanced permeability and retention" effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases.

• Authors: Iryna N Stepanenko, Angela Casini, Fabio Edafe, Maria S Novak, Vladimir B Arion, Paul J Dyson, Michael A Jakupec, Bernhard K Keppler
• Journal: Inorganic chemistry (Inorg Chem) Vol. 50 Issue 24 Pg. 12669-79 (Dec 19 2011) ISSN: 1520-510X [Electronic] United States
• PMID: 22111668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 American Chemical Society

Chemical References

• Antineoplastic Agents
• Benzazepines
• Coordination Complexes
• Cross-Linking Reagents
• Protein Kinase Inhibitors
• Pyridines
• Serum Albumin
• Solutions
• Ruthenium
• Cyclin-Dependent Kinases

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Benzazepines (chemistry, pharmacology)
• Cell Cycle
• Cell Line, Tumor
• Coordination Complexes (chemistry, pharmacology)
• Cross-Linking Reagents (chemistry)
• Crystallography, X-Ray
• Cyclin-Dependent Kinases (antagonists & inhibitors, metabolism)
• Drug Screening Assays, Antitumor
• Drug Stability
• Humans
• Isomerism
• Molecular Structure
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Pyridines (chemistry, pharmacology)
• Ruthenium
• Scattering, Small Angle
• Serum Albumin (chemistry)
• Solutions
• X-Ray Diffraction