TY - JOUR
T1 - Trend in cytotoxic activity of a series of cis-[APtCl2] (A = ethylenediamine methylated at different positions) complexes
AU - Milanesio, Marco
AU - Monti, Elena
AU - Gariboldi, Marzia Bruna
AU - Gabano, Elisabetta
AU - Ravera, Mauro
AU - Osella, Domenico
N1 - Funding Information:
This work was financially supported by Agenzia A.T.F. (Ambiente, Territorio e Formazione, Alessandria). The research was carried out within the framework of the European Cooperation COST D39 (Metallo-Drug Design and Action) and COST B16 action (Multidrug resistance reversal). We thank Dr. Graziana Bagni and Prof. Marco Mascini (University of Florence) for their assistance in the DNA biosensor measurements. Helpful discussions with Prof. Edward Rosenberg (University of Montana, USA) are gratefully acknowledged.
PY - 2008/6/27
Y1 - 2008/6/27
N2 - The study of a series of cis-[APtCl2] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC50 (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl2] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A)PtCl2] complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a -(CH2)n- spacer (n = 2, 4, 6, 8 and 10), L].
AB - The study of a series of cis-[APtCl2] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC50 (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl2] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A)PtCl2] complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a -(CH2)n- spacer (n = 2, 4, 6, 8 and 10), L].
KW - Cisplatin-like complexes
KW - DNA biosensors
KW - Metallopharmaceuticals
KW - Molecular mechanics calculations
UR - https://www.scopus.com/pages/publications/44749093679
U2 - 10.1016/j.ica.2008.02.004
DO - 10.1016/j.ica.2008.02.004
M3 - Article
SN - 0020-1693
VL - 361
SP - 2803
EP - 2814
JO - Inorganica Chimica Acta
JF - Inorganica Chimica Acta
IS - 9-10
ER -