Platinum anticancer complexes

Dinuclear and trinuclear compounds represent a new class of platinum anticancer complexes and are among the most studied platinum compounds in antitumor chemistry. Many of these complexes circumvent cisplatin-resistance mechanisms. In contrast to cisplatin, the polynuclear complexes predominantly form interstrand cross-links. The dinuclear complex [ tranx-PtCl(NH3)2 2 /u.-(H2N(CH2) NH2) ]2+ (l,l/t,t) (17, Figure 9) is antitumor-active and shows no cross-resistance in cisplatin-resistant cell fines. Binding studies sfiowed tfiat DNA binding for this compound is different from that for cisplatin, as illustrated by the increased interstrand cross-linking. However, clinical testing was abandoned because of severe neurotoxicity. 

Bemers-Price, S. J, Frey, U., Ranford, J. D., Sadler, P. J. (1993). Stereospecific hydrogenbonding in mononucleotide adducts of platinum anticancer complexes in aqueous... 

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

The interaction of platinum(II) complexes with various amino acids and simple peptides is relevant to understanding the biological fate of platinum anticancer agents such as mplatin, and this area has been reviewed extensively.258-261... 

There are numerous platinum(IV) complexes with nitrogen donors, most of which have been prepared as potential anticancer drugs or in the study of the reactions of such drugs. These compounds are described below in Section 6.5.6.5. 

Platinum(IV) complexes have been known to be anticancer active since the original studies in this area by Rosenberg.447 Consequently numerous platinum(IV) complexes have been prepared for biological testing. Until recently, the great bulk of these were trans-dihydroxo complexes prepared... 

The anticancer activity of platinum(IV) complexes, and the belief that reduction is needed to initiate this activity, had generated substantial interest in the rates and mechanism of reduction by biologically relevant reductants such as thiols, ascorbic acid, and methionine. Reduction of platinum(IV) to platinum(II) usually proceeds as a single two-electron step and is usually first-order with respect to both platinum(IV) and reductant concentrations. 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

Mackay, F. S. Photoactive platinum azide anticancer complexes, PhD Thesis, University of Edinburgh, Edinburgh, 2006. 

The present volume is the fourth in the series and covers the topics lithium in biology, the structure and function of ceruloplasmin, rhenium complexes in nuclear medicine, the anti-HIV activity of macrocyclic polyamines and their metal complexes, platinum anticancer dmgs, and functional model complexes for dinuclear phosphoesterase enzymes. The production of this volume has been overshadowed by a very sad event—the passing away of the senior editor, Professor Robert W. Hay. It was he who conceived the idea of producing this series and who more than anyone else has been responsible for its continuation. A tribute by one of his many friends, Dr. David Richens, is included in this Volume. 

In conclusion, nucleophilic substitution by H20, Cl, low- and high-molecular-weight thiols, and other nucleophiles plays a major role in the metabolism of platinum complexes. These reactions direct the activation, deactivation, toxification, detoxification, distribution, and excretion of platinum anticancer drugs. Given the large differences in reactivity, and the multiplicity... 

Eastman A, Richon VM. Mechanisms of cellular resistance to platinum coordination complexes. In (McBrien DCH, Slater TF, eds) Biochemical Mechanisms of Platinum Anticancer Drugs 1986 IRL Oxford, UK pp. 91-119. 

Cisplatin (dx-Diamminedichloroplatinum) is a divalent water-soluble platinum containing complex. It reacts directly with DNA, resulting in both intra-and inter-strand cross-links. It also causes DNA breaks and it inhibits DNA replication and RNA transcription. A mechanism for the occurrence of resistance appears to be an increased of the levels of DNA-excision repair enzymes. Cisplatin is used in combination therapies with other anticancer drugs in the treatment of testicular and ovarian cancers and it has also shown high activity against cancers of the bladder, head, neck and endometrium. It is administered intravenously by rapid injection or by continuous infusion. It is for more that 90% bound to... 

Lock, C. J. L. (1980). Structural studies of the hydrolysis products of platinum anticancer drugs, and their complexes with DNA base. In A. E. Martell (ed.), ACS Symposium Series, Vol. 140 Inorganic Chemistry in Biology and Medicine, pp. 209-24. 

Ba[Pt(CN)4] is used in the production of fluorescent X-ray screens.94 Dichlorodihydroxy-diamine- and dichlorodinitratodiamine-platinum(IV) complexes show weak fungicidal activity, but there appears to be no likelihood of them actually being used to this end.95 Other applications of platinum complexes involve their use as anticancer agents, as selective stains in biology, in catalysis, in metallurgy and in photography, described in the relevant chapters of this volume. 

Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

A fourth approach, which has been popular among HPLC chroma-tographers, is to use a simplex optimization algorithm to determine the optimal solvent [27]. This approach was used in the separation of anticancer platinum (II) complexes [78], drug screening [79], and alkaloids [80]. 

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