Amide-based Prodrugs of spermidine-bridged dinuclear platinum. Synthesis, DNA binding, and biological activity

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 51, 2254-2260 Autoři: Hegmans, A., Kasparkova, J., Vrana, O., Kelland, LR., Brabec, V., Farrell, NP. Rok: 2008

Abstrakt

The chemistry and biology of acetyl-protected spermidine-bridged dinuclear platinum complexes [(trans-PtCl(NH3)(2)](2)-mu-NH2(CH2)(3)N(COR)(CH2)(4)NH2]X-2 (R = H, X = C1 (1,1/t,t-spermidine, BBR3571); R = CH3, X = Cl (2); R = CH2 Cl, X = ClO4 (3); R = CF3, 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(NH3)(2)}(2)-mu-trans-Pt(NH3)(2)(NH2(CH2)(6)NH2)(2)](NO3)(4), (8, BBR3464).