The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations.
#NAG SAG CASTRO BEAR SERIES#
Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. Thus, new therapeutical agents are needed. Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Moreover, metal coordination selects anti conformers for the mono-alkyl thioureas, and syn–anti conformers for the di-alkyl thioureas. This is also observed for the corresponding PdII complexes, which, according to the enhancement of the double C–N bond character, present slower syn/anti exchanges. Syn protons of the alkyl-chains are converted into the corresponding anti protons by C–N rotation, which also exchanges external (close to the S atom) to internal N–H (on the opposite side with respect to the S atom) within the NMR timescale.
Mono-alkyl derivatives, in methanol, show equilibria between syn and anti conformers, whereas di-alkyl thioureas show equilibria between the syn–anti and syn–syn conformers (syn and anti indicate the position of the alkyl chain with respect to the S atom over the two amino-branches).
#NAG SAG CASTRO BEAR FREE#
Spectra at variable temperatures of the free thioureas are consistent with hampered rotation around the C–N bonds. The conformational and dynamic behavior in solution, analyzed by several NMR techniques, is compared to that of the free thiourea ligands. The synthesis and characterization of 10 complexes, Cl2 and Cl2 (bipy = 2,2′-bipyridyl phen = 1,10-phenanthroline R-TU = N-alkyl substituted thioureas), is presented.
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