Evaluation of antiproliferative activities and apoptosis induction caused by copper(II)-benzothiazolesulfonamide complexes in Jurkat T lymphocytes and Caco-2 cells.
Two copper(II) complexes with a benzothiazolesulfonamide ligand, [Cu(L)2(py)2] (1) and [Cu(en)2(L)2] (2) [HL is N-2-(4-methylbenzothiazole)toluenesulfonamide, py is pyridine, en is ethylenediamine], were prepared and then characterized with the aid of X-ray crystallography and spectroscopy. Whereas the copper(II) ion in 1 presents a square-planar geometry, in 2 it has a distorted octahedral environment. In addition, although the ligand is monodentate in both complexes, it exhibits different coordination behavior in each, interacting through the benzothiazole nitrogen atom in 1 and through the sulfonamide nitrogen atom in 2. The propensity for binding of 1 and 2 to calf thymus DNA was studied by thermal denaturation, viscosimetry, and cyclic voltammetry. The ability of the complexes to cleave DNA was studied in vitro through ascorbate activation and was tested by monitoring the expression of the yEGFP gene containing the RAD54 reporter. Moreover, their antiproliferative activity was verified in two cellular models: yeast and human tumor cells in culture. While 1 was found to be the more active cleaving agent in vitro, 2 showed a higher propensity for inflicting DNA damage at the cellular level. The biological studies carried out with human tumor cells, namely, colon adenocarcinoma Caco-2 cells (HTB-37) and leukemia Jurkat T lymphocytes (TIB-152), confirmed that both compounds inhibit the growth of these cell lines, although 2 is more effective. This difference is associated with the latter compound's greater ability to induce cell death by apoptosis.
González-Alvarez
Marta
M
Departament de Química Inorgànica, Facultat de Farmàcia, Universitat de València, Avda. Vicente Andrés Estellés s/n, 46100, Burjassot, Spain.
Alzuet
Gloria
G
Borrás
Joaquín
J
del Castillo-Agudo
Lucas
L
Montejo-Bernardo
Jose Manuel
JM
Gutiérrez-Rodríguez
Angel
A
García-Granda
Santiago
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018938:Caco-2 Cells; D002413:Cations, Divalent; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D009152:Mutagenicity Tests; D013057:Spectrum Analysis; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002413:Cations, Divalent; D013449:Sulfonamides; C078551:2-benzothiazolesulfonamide; D003300:Copper; D004247:DNA; C427203:calf thymus DNA