Abstract
Three novel platinum(IV) complexes cis,cis,trans-[Pt(HL1-3)Cl2(OH)2] 1b-3b (HL = 2-hydroxy-3-[(R1-amino)(pyridin-2-yl)methyl]-1,4-naphthoquinone, R1 = n-butyl, HL1; n-heptyl, HL2 and n-decyl, HL3) have been obtained from the oxidation of the respective precursors cis-[Pt(HL1-3)Cl2] 1a-3a. Cyclic voltammetry studies of 1b-3b in MeCN showed the quasi-reversible naphthoquinonate (NQO-, i.e. , L-) redox process and irreversible process attributed to the reduction of the Pt4+/Pt2+ pair, at potentials about 400 mV less negative than for the cisplatin precursor cis,cis,trans-[Pt(NH3)2Cl2(OH)2]. Hydrogen bond interaction between the naphthoquinone 2-hydroxyl group and an axially coordinated hydroxide ligand in 1b-3b has been proposed to favor the Pt4+/Pt2+ reduction. The cytotoxicity studies against four human cancer cell lines have shown that in general the platinum(IV) and platinum(II)derivatives exhibit the same cytotoxic profile and are all more active than cisplatin. The lowest in vitro IC50 values have been observed for 2b-3b, which bear ligands with the largest R1 groups (HL2-HL3) being the most lipophilic. Furthermore similar IC50 values for platinum(II) and platinum(IV) complexes of the same ligands have been associated with rapid in vitro reduction of the latter complexes to afford 1a-3a.
Highlights
Cisplatin (cis-diaminodichloro-platinum(II)) is a well known antineoplastic agent[1] that acts mainly through DNA binding, interrupting replication and transcription processes and inducing apoptosis.[2]
Two factors are critical for their activation: the Pt4+/Pt2+ reduction potential of the complex and the rate of reduction,[6] and both can be tuned by judicious choice of the carrier and axial ligands, the latter playing an important role in the pharmacokinetic properties of these complexes.[7,8]
We describe the synthesis, characterization, electrochemical and cytotoxic studies of the novel complexes [Pt(HL)Cl2(OH)2] 1b-3b, shown in Scheme 1
Summary
Cisplatin (cis-diaminodichloro-platinum(II)) is a well known antineoplastic agent[1] that acts mainly through DNA binding, interrupting replication and transcription processes and inducing apoptosis.[2] Even though cisplatin has been currently used in cancer treatment, side effects such as nephrotoxicity and acquired resistance have limited its effectiveness and motivated the search for new Pt-based drugs able to overcome these drawbacks.[3,4]. One of the problems associated with platinum(II) complexes, including cisplatin, is their deactivation by sulfur containing species,[5] which prevents their uptake into the cell and DNA binding.
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