Hydrolysis platinum complexes

Hydrogen bonding between an SiOH group and fluorine occurs in the platinum complex 44 [prepared by hydrolysis of a bis(alkylidene)-silacyclopropane] in which the SbF6 anion hydrogen bonds to the platinum-containing cation (O - F distance 2.77(2) A) (249). The platinum complex 45 is not reported (250) to form hydrogen bonds, and a more recent study (210) has confirmed that there do not appear to be any OH OH or OH tt interactions. 

The aquation rate is mainly determined by the trans effect of the ligand trans to Cl. The aquation rate constants of some platinum complexes are listed in Table I. For example, the rate of hydrolysis of CP trans to c-C6HnNH2 in complex 14, a metabolite of the oral drug 11 (42), is about twice as fast as trans to NH3 (43). 

Since the discovery of the antitumor activity of m-PtCNFhuC (cisplatin, cd-DDP) by Rosenberg et al. [1], the interactions of cisplatin with nucleotides and nucleobases have attracted attention towards gaining an understanding of the mechanism of the antitumor activity of cisplatin at a molecular level. In the course of such studies, dark-blue platinum complexes called platinum blues were obtained when hydrolysis products of cis-... 

From this evidence, Langford argued that the X group is essentially completely dissociated and acts as a solvated anion in the transition state of acid hydrolysis and that water is at most weakly bound in the transition state. Another example from reactions of square-planar platinum complexes is given in Section 12-6-2. 

The fluorescent complex [Ru(II)(3,4,7,8-tetramethylphen)3]Cl2 is readily taken up by P388 leukemia cells in culture and is visible on the cell surface, in the cytoplasm, and in the nucleus, but it does not exhibit antitumor activity in vivo (11). The platinum complexes [Pt(en)(oxalate)], [Pt(NH3)2(H20)2l (as the dinitrato complex), and [Pt(en)3] + also cause convulsions in animals (12) the latter two complexes are positively charged and relatively inert and the former is neutral and presumably undergoes an activation step before it binds to the neuromuscular junction. Curiously, the related malonato complex is not a neurotoxin. Care is taken in the clinic to administer cisplatin in saline solutions to avoid hydrolysis and minimize the production of neurotoxic aqua or hydroxobridged Pt(II) species. 

The cytotoxicity of cisplatin originates from the hydrolysis facility of the chlorine, its binding to DNA, and the formation of covalent cross-links. One disadvantage of cisplatin is its limited solubility in aqueous solutions and its intravenous administration. Platinum complexes with distinctively different DNA binding modes from those of cisplatin may provide higher antitumor activity against cis-platin-resistant cancer cells. 

In principle, it should be possible to vary the activity of platinum complexes not only by altering the thermodynamics of platinum binding to DNA, but also by altering the rate at which the equilibrium of equation 1 is attained. The kinetics of this hydrolysis reaction will be dictated by the trans-effect, that is, by the ability of the ligand lying trans to the chloride to increase the rate of the chloride ion substitution reactions. 

Hydrolysis reactions of antitumor platinum complexes and an estimate of the species present in plasma and cytoplasm (reproduced by permission from Reference 51). 

Such a structure has never been observed for cts-DDP binding to DNA, however. DNA-protein and interstrand erosslinks formed by platinum complexes have been the focus of many attempts to explain cytotoxicity and antitumor behavior. " The technique of alkaline elution, in which crosslinked DNA-DNA strands or DNA-protein molecules bind to filter paper following denaturation under basic conditions, sensitively and easily reveals such adducts. trans-DDV forms such adducts more rapidly than the cis isomer, perhaps because of its faster ehloride-ion hydrolysis rates (see above) and a more favorable geometry, but they also seem to be repaired more rapidly in eells. As will be shown, interstrand and DNA-protein crosslinks are a small minority of adduets formed by cisplatin, and their contribution to the cytotoxic and anticancer properties of... 

The hafnium complexes 9 and 16, respectively, with their preformed 1,3,5-triphosphinine ligands, are suitable substrates for the preparation of the nickel complex 24 [29]. In addition to the complexes with 7] -coordination, a platinum complex with fj -coordination is known. Complex 25, characterized spectroscopically in solution, undergoes hydrolysis with oxidation of the phosphorus atoms of the triphosphinine to afford the f] -platinum complex 26 possessing a hexahydrotriphosphinine ligand in the boat form as demonstrated by an X-ray crystallographic analysis [30]. 

In aqueous solution cisplatin is known to undergo spontaneous hydrolysis. The reaction produces species such as monoaquo platinum and diaqua platinum complexes, as shown in Eq. 8.1, arising from nucleophilic substitution in water. 

It should increase delivery of the bioactive moiety and decrease toxicity. In aqueous solutions, cisplatin hydrolyzes with a reaction half-life of nine hours at room temperature or 2.4 hours at 37 °C. Cisplatin hydrolyzes in the body forming a wide variety of platinum-containing agents, none of which is as active as cisplatin itself and most of which exhibit increased toxicity to the body. Formation of these hydrolysis products increases the amount of platinum complex that must be added to effect desired tumor reduction. Consequently, this increases the amount of platinum complexes that must be processed by the body. The polymeric structure should also shield the platinum moiety from unwanted hydrolysis increasing the concentration of platinum in the beneficial form that is retained in the body thus permitting lower effective doses of the drug to be used. The nature of the more hydrophobic polymer chain should also act to protect the platinum moiety from ready attack by water. 

Other metallocenes are active in vitro, e.g. CP2VCI2 and Cp2NbCl2 [7], but have not reached clinical trials. Attempts to modify the aqueous solubility and stability of titanocenes are underway in several laboratories [15, 16]. Another Ti(IV) complex, budotitane (6, Fig. 2.2), was the first non-platinum complex to be approved for clinical trials, but poor solubility and hydrolysis made formulation difficult even in micelles, and the trials were abandoned [17]. 

The hydrolysis profile of the bifunctional dinuclear platinum complex [ trans-PtCl( 5NH3)2 2(jr - NH2(CH2)6 NH2)f+ (l,l/t,t( = 6), 10, the prototype of a novel class of potential antitumor complexes, has recently been studied by using [ H, N] HSQC NMR spectroscopy [62]. The process of the hydrolysis is sketched in Scheme 5.2. An interesting finding is that the position of the... 

The pATa values for the 2 and 2" of the multinuclear platinum complexes 1,1/t,t ( = 6) and l,0,l/t,t,t ( = 6) are lower than that for w-[Pt(NH3)2 C1(H20)]+, and is also lower than the reported values for [Pt(dien)(H20)] and [Pt(NH3)3 (H20)] + (Table 5.2) [62,64]. It is inferred that the smaller extent of hydrolysis and lower pATa values (about 5.62) of the monoaqua chloro speeies eompared to eisplatin (6.41) will have a major influence on the differ-enees in the speeiation and reaetivity of these platinum antitumor complexes under biologieal eonditions. The lower pAfa value suggests that the monoaqua monochloro complex T, the major hydrolysis product of 1, will be mainly in the less reaetive hydroxo form 4 under physiological pH [62]. 

The dimethyl(hydroxo)platinum complex 1008 is obtained from oxidation of 1006 with O2 followed by hydrolysis of the hydroperoxoplatinum complex 1009 (Scheme 126). Oxidation of 1006 in aqueous media also yields 1008. 

Considerable advances in the detection of intracellular metabolites have been made and a detailed description is available for complexes containing 1,2-diaminocyclohexane as carrier ligand [124, 125]. In these studies the widespread interaction with amino acids has been demonstrated and the hydrolysis of [Pt(malonato) (dach)] occurs without the requirement of enzymatic activation, as originally hypothesized. Biotransformation of platinum complexes has also been demonstrated by NMR studies [126]. These studies are an important complement to those of the DNA interactions discussed in Chapter 4, in terms of the overall objective of describing the intracellular chemistry of platinum complexes as fully as possible. 

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