Synthesis and in Vitro and in Vivo Antitumor Activity of a Series of Trans Platinum Antitumor Complexes

Abstract

The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.

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

“…Interestingly, however, compound 1 did not show any statistically significant effect in CH1 tumor progression relative to control mice. These results indicate that compound 2 shows a promising level of in vivo antitumor activity against a human tumor xenograft in comparison to both the Pt(II) counterpart (compound 1) and transplatin (Kelland et al, 1995).…”

“…The resistant cell lines show acquired resistance to cisplatin and were selected with regard to the three major mechanisms of resistance to the drug. In addition, these cell lines have been used previously to identify novel platinum complexes capable of circumventing cisplatin resistance (Kelland et al, 1992(Kelland et al, , 1994(Kelland et al, , 1995. Because cellular and molecular pharmacology studies are essential to understand the relationships between structure and anticancer properties, we have compared the cellular accumulation, DNA binding, interstrand cross-linking efficiency, apoptosis induction, and binding to serum albumin and plasma proteins of the transPt(IV) complex (compound 2) with that of its corresponding trans-Pt(II) analog (compound 1).…”

Cisplatin: mode of cytotoxic action and molecular basis of resistance

“…The exact level of cisplatin resistance in patients is difficult to define, but at least a twofold resistance is inferred from clinical studies, primarily since responses have been observed when the standard clinical dose of cisplatin is doubled in drug-intensive therapy protocols (Ozols et al, 1984Schilder and Ozols, 1992). In general, resistance to cisplatin may be substantially greater, as judged from studies with tumor cell lines established from clinically refractory tumors, which require cytotoxic concentrations as much as 50-100-fold in excess of those needed for sensitive tumor cells (Hills et al, 1989;Kelland et al, 1995;Hagopian et al, 1999). Thus, the problem posed by cisplatin resistance appears to be more severe than has been acknowledged in the past.…”

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5′-GMP

“…The synthesis of the asymmetric trans-platinum(II) complexes was accomplished through treatment of the symmetric tetra-amine complex with concentrated hydrochloric acid as illustrated in Scheme 1, based on literature procedures [23]. The complexes where fully characterized using 1 H, 195 Pt NMR (Table 1), IR, X-ray diffraction and elemental analysis.…”