Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex:trans-[PtCl₂(OH)₂(Dimethylamine) (Isopropylamine)]

Abstract

The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl 2 (OH) 2 (dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl 2 (dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand crosslinks in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2. Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins.

Anti-proliferative properties of commercial Pelargonium sidoides tincture, with cell-cycle G0/G1 arrest and apoptosis in Jurkat leukaemia cells

“…The results reflect the treatment of the Jurkat cells with the GI 50 concentration of the extract. Similar results have been observed with platinum-containing compounds (Pèrez et al 2003) and piplartine (Bezerra et al 2007). It has been suggested that the pathways leading to apoptosis and necrosis are interconnected and that factors like energy availability as well as metabolic condition of the cells may play a role in deciding apoptotic or necrotic cell death .…”

Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

“…Trans,trans,trans-[PtCl 2 (OH) 2 (dma)(ipa)], 1, and trans-[PtCl 2 (ipa)(ma)], 2, were prepared using previously described procedures [24,25]. Guanosine-5′-monophosphate (GMP), cytidine-5′-monophosphate (CMP) and 9-methyladenine (9MeA) were purchased from Sigma-Aldrich and adenosine-5′-monophosphate (AMP) from Acros Organic.…”

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

“…Compounds of all these classes lack cross-resistance to cisplatin in cellular models of acquired cisplatin resistance (Farrell et al, 1992;Kelland et al, 1995;Coluccia et al, 1999;Pérez et al, 2003;Najajreh et al, 2006). Furthermore, some of these compounds display a cytotoxicity profile that barely correlates with that of cisplatin in the cell line panel of the NCI comprising cells from a wide variety of malignancies (Farrell, 1996), and some even proved to be active in in vivo models with intrinsic or acquired resistance to cisplatin (Kelland et al, 1995;Coluccia et al, 1999), raising the hope that an antineoplastic drug with a different clinical activity profile might emerge from these nonclassic platinum agents.…”

“…Cytotoxicity higher than or at least equal to that of the corresponding cis isomer and/or that of cisplatin has mostly been taken as sufficient. 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.…”