Solution behaviour and biological activity of bisamidine complexes of platinum(II)

Abstract

A series of platinum(II) amidine complexes were previously prepared with the aim of obtaining a new class of platinum-based antitumour drugs. This series includes compounds of the type cis--[PtCl2{Z-HN=C(NHMe)Me}2] and trans-[PtCl2{Z-HN=C(NHMe)Me}2] (1, 2), cis-[PtCl2{E-HN=C(NMe2)Me}2] and trans-[PtCl2{E-HN=C(NMe2)Me}2] (3, 4), cis-[PtCl2{Z-HN=C(NHMe)Ph}2] and trans-[PtCl2{Z-HN=C(NHMe)Ph}2] (5, 6), and cis-[PtCl2{HN=C(NMe2)Ph}2] and trans-[PtCl2{HN=C(NMe2)Ph}2] (7, 8). The reactions with dimethyl sulfoxide were studied for complexes 5-8; the formation of cationic species containing coordinated dimethyl sulfoxide was demonstrated by NMR experiments and electrospray ionization mass spectrometry. In this work, the amidine platinum(II) complexes were tested for their in vitro cytotoxicity on a panel of various human cancer cell lines. The results indicate that the benzamidine complex 8 was the most effective derivative also circumventing acquired cisplatin resistance as demonstrated by chemosensitivity tests performed on cisplatin-sensitive and cisplatin-resistant cell lines. The studies concerning the cellular DNA damage on both parental chemosensitive and resistant sublines suggest for the new trans-amidine complex a different mechanism of action compared with that exhibited by cisplatin.

Synthesis, Characterization, and In Vitro Antitumor Activity of New Amidineplatinum(II) Complexes Obtained by Addition of Ammonia to Coordinated Acetonitrile

“…The activity of the compounds presently investigated appears to be in contrast with the reported inactivity of analogous platinum complexes with unsubstituted amidine ligands derived from benzonitrile. [18] Although different cell lines were employed, and this could be the reason for the difference in behavior, we also want to note that the medium used to dissolve the compounds was different. In the work with benzamidine complexes, dimethylsulfoxide was used to dissolve the compounds, and it is well known that this solvent can cause fast solvation with the formation of cationic species that could be biologically inactive.…”

Synthesis, characterization and cytotoxic activity of substituted benzyl iminoether Pt(II) complexes of the type cis- and trans-[PtCl2{E-N(H)C(OMe)CH2–C6H4–p–R}2] (R=Me, OMe, F). X-ray structure of trans-[PtCl2{E-N(H)C(OMe)CH2–C6H4–p–F}2]

“…Within the class of amidine platinum(II) derivatives of the type cis-and trans-[PtCl 2 {N(H)@C(NRR 0 )R 00 } 2 ] (R = H, R 0 = Me; R = R 0 = Me; R 00 = Me, Ph) that we have recently reported [11], those with benzamidine ligands are much more biologically active than the corresponding acetamidines possibly owing to the more lipophilic properties of the phenyl ring. Furthermore, it was also shown that the N-Me 2 disubstituted benzamidines are more cytotoxic than the NHMe monosubstituted ones; this could be due to the persistence, in the latter case, of intramolecular hydrogen bonds between the NH amidine protons and the metal-coordinated chlorides, forming a six-membered ring.…”

“…Other new classes of antitumor trans-platinum drugs have been recently reported bearing non-leaving ligands such as iminoethers [10] and amidines [11]. Several studies, reported by Coluccia and Natile, have been focused on the cytotoxic activity of the iminoether complex trans-[PtCl 2 {E-N(H)@C(OMe)Me} 2 ], which is endowed with significant antitumor activity, even against also cisplatinresistant tumor cells, displays an enhanced cellular uptake with respect to cisplatin [12,13] and has the ability of damaging cellular DNA [14].…”

Chemistry and Biological Activity of Platinum Amidine Complexes

“…[96] In fact, the benzamidine platinum(II) derivatives were found to be endowed with a better cytotoxic profile than the corresponding acetamidines. The presence of a phenyl ring in the coordination sphere of the metal most likely establishes a favorable hydrophilic/lipophilic balance that may enhance cellular uptake.…”