TY - JOUR
T1 - Trans-cis-cis-[RuCl2(DMSO)2(2-amino-5-methyl-thiazole)2], (PMRu52), a novel ruthenium(II) compound acting as a strong inhibitor of cathepsin B
AU - Mura, Pasquale
AU - Camalli, Mercedes
AU - Casini, Angela
AU - Gabbiani, Chiara
AU - Messori, Luigi
N1 - Funding Information:
Thanks are due to Prof. Marcello Colapietro, Department of Chemistry, Rome1 University “La Sapienza” – Rome – Italy, for the X-ray data collection of ( I, PMRu52 ). Thanks are also due to the referees for theirs very useful suggestions. We thank Dr. Elena Michelucci from CISM (University of Florence) for recording the ESI-MS spectra. A.C. thanks SNSF for funding (Ambizione project n°PZ00P2-121933).
PY - 2010/2
Y1 - 2010/2
N2 - A novel ruthenium(II) compound, trans-cis-cis-[Ru(II)Cl2(DMSO)2(2-amino-5-methyl-thiazole)2], (I), PMRu52 hereafter, that may be obtained from the previously described (cis and trans)-[Ru(II)Cl2(DMSO)4] complexes, was designed, synthesized and characterised. The single crystal X-ray structure shows a roughly regular octahedral environment for the ruthenium(II) center with the two chloride ligands in trans and the other two pairs of identical ligands in cis. The behaviour of PMRu52 in phosphate buffer, at pH = 7.4, was characterised spectroscopically as well as its interactions with a few representative biomolecules. Tight ruthenium binding to serum albumin was established by joint use of spectroscopic and separation methods. Afterward, the reactions of PMRu52 with the model proteins ubiquitin and cytochrome c were monitored through electrospray ionisation mass spectrometry (ESI-MS) methods: the formation of metallodrug-protein adducts was documented in detail and the fragmentation patterns of PMRu52 were defined. Finally, the ability of PMRu52 to affect the activity of cathepsin B, a well known cysteine protease, was evaluated in vitro and a pronounced enzyme inhibition highlighted, with an IC50 value of 5.5 μM. This latter finding is of particular interest as cathepsin B constitutes an attractive "druggable" target for cancer, rheumatoid arthritis and other important diseases.
AB - A novel ruthenium(II) compound, trans-cis-cis-[Ru(II)Cl2(DMSO)2(2-amino-5-methyl-thiazole)2], (I), PMRu52 hereafter, that may be obtained from the previously described (cis and trans)-[Ru(II)Cl2(DMSO)4] complexes, was designed, synthesized and characterised. The single crystal X-ray structure shows a roughly regular octahedral environment for the ruthenium(II) center with the two chloride ligands in trans and the other two pairs of identical ligands in cis. The behaviour of PMRu52 in phosphate buffer, at pH = 7.4, was characterised spectroscopically as well as its interactions with a few representative biomolecules. Tight ruthenium binding to serum albumin was established by joint use of spectroscopic and separation methods. Afterward, the reactions of PMRu52 with the model proteins ubiquitin and cytochrome c were monitored through electrospray ionisation mass spectrometry (ESI-MS) methods: the formation of metallodrug-protein adducts was documented in detail and the fragmentation patterns of PMRu52 were defined. Finally, the ability of PMRu52 to affect the activity of cathepsin B, a well known cysteine protease, was evaluated in vitro and a pronounced enzyme inhibition highlighted, with an IC50 value of 5.5 μM. This latter finding is of particular interest as cathepsin B constitutes an attractive "druggable" target for cancer, rheumatoid arthritis and other important diseases.
KW - Anticancer
KW - Cathepsin B
KW - Ruthenium (II) compounds
UR - http://www.scopus.com/inward/record.url?scp=71849112054&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2009.10.002
DO - 10.1016/j.jinorgbio.2009.10.002
M3 - Article
C2 - 19939460
AN - SCOPUS:71849112054
SN - 0162-0134
VL - 104
SP - 111
EP - 117
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
IS - 2
ER -
