Antioxidant-prooxidant properties of a new organoselenium compound library.
The present study describes the biological evaluation of a library of 59 organo-selenium compounds as superoxide (O₂⁻) generators and cytotoxic agents in human prostate cancer cells (PC-3) and in breast adenocarcinoma (MCF-7). In order to corroborate that the biological activity for selenium compounds depends on the chemical form, a broad structural variety is presented. These structures include selenocyanates, diselenides, selenoalkyl functional moieties and eight newly synthesized symmetrically substituted dithioselenites and selenylureas. Eleven of the derivatives tested showed high levels of superoxide generation in vitro via oxidation of reduced glutathione (GSH) and nine of them were more catalytic than the reference compound, diselenodipropionic acid. Eighteen of the library compounds inhibited cell growth more than or similar to reference chemotherapeutic drugs in PC-3 and eleven were more potent cytotoxic agents than etoposide in the MCF-7 cell line. Considering both parameters (superoxide generation and cell cytotoxicity) compounds B1, C6 and C9 displayed the best therapeutic profiles. Considering that many diselenide compounds can generate superoxide (O₂⁻) in vitro via oxidation of GSH and other thiols, the analogue B1, that contains a diselenide moiety, was selected for a preliminary mechanistic investigation, which revealed that B1 has apoptogenic effects similar to camptothecin mediated by reactive oxygen species (ROS) in lymphocytic leukemia cells (CCRF-CEM) and affected the MCF-7 cell-cycle in G₂/M and S-phases.
Plano
Daniel
D
Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Baquedano
Ylenia
Y
Ibáñez
Elena
E
Jiménez
Iosu
I
Palop
Juan Antonio
JA
Spallholz
Julian E
JE
Sanmartín
Carmen
C
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D054852:Small Molecule Libraries
D000970:Antineoplastic Agents; D000975:Antioxidants; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries