Metals in anticancer therapy: copper(II) complexes as inhibitors of the 20S proteasome.
Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu(L(I))Cl] (1), [Cu(L(I))OAc] (2), and [Cu(HL(I))(L(I))]OAc (3), where HL(I) is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV-visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1-3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuL(I)](+) as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.
Hindo
Sarmad Sahiel
SS
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
Frezza
Michael
M
Tomco
Dajena
D
Heeg
Mary Jane
MJ
Hryhorczuk
Lew
L
McGarvey
Bruce R
BR
Dou
Q Ping
QP
Verani
Cláudio N
CN
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors
D000970:Antineoplastic Agents; D010636:Phenols; D061988:Proteasome Inhibitors; D003300:Copper; D046988:Proteasome Endopeptidase Complex