Amide-Based Prodrugs of Spermidine-Bridged Dinuclear Platinum. Synthesis, DNA Binding, and Biological Activity

Abstract

The chemistry and biology of acetyl-protected spermidine-bridged dinuclear platinum complexes [{trans-PtCl(NH 3 ) 2 ] 2 -μ-NH 2 (CH 2 ) 3 N(COR)(CH 2 ) 4 NH 2 ]X 2 (R = H, X = Cl (1,1/t,t-spermidine, BBR3571); R = CH 3, X = Cl (2); R = CH 2 Cl, X = ClO 4 (3); R = CF 3, X = Cl (4)) are compared with their carbamate analogues. The compounds are potential prodrugs for the parent compound 1, a highly potent antitumor agent. At pH 6-8 hydrolysis of the blocking group with the release of the "parent" protonated species follows the order 4 > 3 ≫ 2. For 4, rate constants for the deprotection increase in this pH range. The DNA binding profile of 4 is similar to the Boc derivative, confirming the central influence of charge on DNA binding properties. The differences in cytotoxicity for the protected compounds in ovarian carcinoma cell lines sensitive and resistant to cisplatin cannot completely be explained by spontaneous release of 1,1/t,t-spermidine at physiological pH. Inherent cytotoxicity and cell line specificity may contribute to the observed behavior. The properties of the compounds present them also as possible "second-generation" analogues of the clinically relevant trinuclear complex [{trans-PtCl(NH 3 ) 2 } 2 -μ-trans-Pt(NH 3 ) 2 (NH 2 (CH 2 ) 6 NH 2 ) 2 ](NO 3 ) 4 , (8, BBR3464).

Improving platinum(II)-based anticancer drug delivery using cucurbit[n]urils

“…In this case, CB [7] had no significant affect on the cytotoxicity of the metal complex. Similarly, for BBR3571, a dinuclear platinum complex with potent in vitro cytotoxicity in a number of cisplatin sensitive and resistant cancer cell lines [60][61][62][63][64][65], the metal complex has identical IC 50 values (0.0115 lM) in the L1210 line with and without CB [7]. In the L1210/DDP resistant line only a slight decrease in cytotoxicity is observed, IC 50 values of 0.0075 and 0.009 lM for the free and encapsulated metal complex, respectively [66].…”

Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2μ-dpzm]2+ and its implications for anticancer drug delivery

“…The A2780 and A2780cis cell lines have been well studied as models for measuring platinum drug cytotoxicity, although the conditions under which the assays have been conducted vary substantially; incubation times range between 48 and 96 h, with an initial plating of 1000-10,000 cells per well, and a variety of substrates in the medium [31][32][33][34][35][36].…”

Platinum(II) oxalato complexes with adenine-based carrier ligands showing significant in vitro antitumor activity

“…In the case of [Pt(pyrr)Cl 2 ] complex, where pyrr stands for both 2(S)-aminomethylpyrrolidine and 2(R)-aminomethylpyrrolidine enantiomers, the in vitro cytotoxicity against human ovarian carcinoma cells (A2780) is comparable with cisplatin, while it was determined as higher than that of cisplatin against A2780R cells (a cisplatin-resistant counterpart of A2780) [19]. Finally, spermidine-bridged dinuclear platinum(II) complexes represent an alternative to the known platinum-based drugs, since these compounds showed promising biological properties (in vitro cytotoxicity testing against ovarian carcinoma cells both sensitive and resistant to cisplatin) [20].…”