Antineoplastic activity of novel N-1-sulfonypyrimidine derivatives.
We evaluated the potential activity of novel N-1-sulfonyl derivatives of pyrimidine bases uracil and cytosine on pancreatic carcinoma cells (MIAPaCa2), colon carcinomas cells (HT-29, CaCo2), cervical carcinoma cells (HeLa) and poorly-differentiated cells from lymph node metastasis of colon carcinoma (SW-620). The cytotoxicity of N-1-sulfonylpyrimidine derivatives was analyzed with the MTT cell survival assay and their antiproliferative activity was measured via radioactive precursors incorporation assay. The N-1-sulfonylpyrimidine derivatives affected the growth of all examined cell lines at concentrations of 10(-8)-10(-5) M, by 25-70%. Growth inhibition depended on the tumor cell line type and the concentration of investigated compounds. The compounds 2, 4, 7, 8 and 9 inhibited DNA, RNA and protein synthesis in CaCo2, MIAPaCa2 and HeLa cells. The exposure of tumor cells in vitro to compounds 2, 4, 7, 8, 9, 10 and 11, at the 10(-6) M concentration, caused both morphological (condensation of chromatin, cell shrinkage), as well as biochemical changes (ladder pattern of DNA fragmentation and exposure of phosphatidylserine on outer lipid bilayer plasma membrane) characteristic of apoptosis. After 24 hours of the N-1-sulfonylpyrimidine derivative application, the p53 oncoprotein expression could not be detected by immunocytochemical analysis. On the basis of present results it can be concluded that novel N-1-sulfonylpyrimidine derivatives are promising antitumor agents with a strong antiproliferative activity and an ability to induce apoptosis in treated tumor cells.
Glavas-Obrovac
L
L
Department of Nuclear Medicine, Clinical Hospital Osijek, Croatia. obrovacg2@hotmail.com
Karner
I
I
Zinic
B
B
Pavelic
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents / Q000494:pharmacology; D003596:Cytosine / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008856:Microscopy, Fluorescence; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004396:Coloring Agents; D011743:Pyrimidines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014498:Uracil; D012313:RNA; D003596:Cytosine; D004247:DNA; C022616:thiazolyl blue