Activity and DNA binding of new organoamidoplatinum (II) complexes

Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)(2)L-2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour ac tivity examined by a range of in vitro, cellular and animal studies. All Cl ass 1 compounds exhibited activity comparable to cisplatin in mouse leukemi a L1210 cells, but were at least 8-fold more active against the cisplatin-r esistant L1210/R line. The lead compound 1a (R=p-HC6F4) caused nearly compl ete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibi ted similar DNA reactivity to cisplatin, resulting in virtually identical D NA sequence specificity as cisplatin, and had similar time and concentratio n dependency of interstrand crosslinks. Compared with cisplatin, 1a showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/ R line. The activity of 1a, therefore, appears to be due at least in part t o a greater cellular uptake into tumour cells, particularly cisplatin-resis tant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity co mpared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans ami ne ligands, and further study of both classes of compounds is warranted.