Platinum complexes with imino ethers or cyclic ligands mimicking imino ethers: synthesis, in vitro antitumour activity, and DNA interaction properties

Abstract

Both trans- and cis-[PtCl(2)(NH(3))(L)] compounds have been synthesized, L representing either the imino ether HN=C(OMe)Me having a Z or E configuration at the C=N double bond, or the cyclic ligands N = C(OMe)CH2CH2CH2 and N = C(Me)OCH2CH2 (compounds 1-4 for trans geometry and 5-8 for cis geometry, respectively). The cyclic ligands mimic the imino ether ligands but, differently from imino ethers, cannot undergo change of configuration. In a panel of human tumor cells, trans compounds inhibit growth much more than transplatin. Moreover, compound 1 in most cases is less active than 2, and 1 and 2 are less active than 3 and 4, respectively. For cis compounds with imino ethers, the activity is reduced (5) or unaffected (6) with respect to cisplatin. Moreover, unlike trans compounds, substitution of cyclic ligands (7,8) for imino ethers (5,6) generally decreases the activity. This determines, for compounds with cyclic ligands, an unusual inversion of the cis geometry requirement for activity of platinum(II) species. Importantly,1-4 and 5-8 partially circumvent the multifocal cisplatin resistance of A2780cisR cells, and 1-4 also overcome resistance from reduced uptake of 41McisR cells. DNA interaction regioselectivity of 1-4 and 5-8 is not substantially modified with respect to transplatin and cisplatin. However, both imino ethers and cyclic ligands slow down the DNA interstrand cross-link reaction, ( E)-HN=C(OMe)Me and N = C(Me)OCH2CH2 decreasing also its extent. Therefore, DNA interaction of 1-4 and 5-8 appears to be characterized by persistent monoadducts (1-4), and by monoadducts and/or intrastrand cross-links structurally different from those of cisplatin (5-8). This study demonstrates that ligand configuration modulates the activity of both trans and cis compounds, and supports the development of platinum drugs based on their coordination chemistry to combat cisplatin resistance.

Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands

“…Each of the following classes of active trans complexes recognized so far includes at least one representative with proved antitumor activity in an in vivo model: 1) platinum(II) complexes with aromatic N-heterocyclic ligands such as thiazole or quinoline (Farrell, 1996); 2) platinum(II) complexes with one or two iminoether ligands (Coluccia et al, 1995); 3) platinum(IV) complexes with one ammine and one aliphatic amine ligand (Kelland et al, 1995); 4) asymmetric platinum complexes with one branched aliphatic amine, such as isopropylamine, and another, nonbulky amine ligand (Pérez et al, 2003); and 5) cationic and neutral platinum(II) complexes with cycloaliphatic amines such as piperidine or piperazine (Najajreh et al, 2006). Platinum(II) complexes with cyclic ligands mimicking iminoethers (Intini et al, 2004) and with acetimine ligands (Boccarelli et al, 2006) have been reported as further classes, based on cytotoxicity data only.…”

Platinated Copper(3‐Clip‐Phen) Complexes as Effective DNA‐Cleaving and Cytotoxic Agents

“…[24] The second step then consists of the addition of 1 equivalent 3-ClipPhen to 7, giving rise to the precipitation of pure product 1. The preparation of compound 2 first requires the activation of cisplatin via the removal of one chloride anion using 1 equivalent of AgNO 3 .…”

Synthesis, crystal structures and cytotoxicities of some transition metal complexes with N-[2-{(pyridin-2-ylmethylidene)amino}ethyl]acetamide

“…Since the discovery of the antitumor activity of cisplatin, cis-[PtCl 2 (NH 3 ) 2 ], by Rosenberg et al, thousands of platinum complexes have been synthesized and tested for antitumoral activity [1][2][3]. Cisplatin and its analogue, carboplatin, have been widely and successfully used for the treatment of different types of cancer.…”