Platinum complexes anticancer drugs

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]. 

Finally, there are sqnare-planar Pt antitumor ammine complexes (see Platinum-based Anticancer Drugs) with the most well known being ds -dichlorodiammineplatinum(II) (cw-DDP) ds -PtCl2(NH3)2. When dissolved in aqueous solution, the chloro ligands can be partially or completely snbstituted by either H2O or OH, and the pH-dependent kinetics and equilibria have been measnred. ... 

Platinum-based Anticancer Drugs). The latter disrupts mutant DNA by interstrand attachment to two adjacent guanine bases. Previously, it had been believed that the carboxylato complexes could not biud to DNA in this fashion. This may prompt further investigation of the antitumor activity of the rhodium complexes, which induce fewer harmful side effects than the platinum complexes. 

Maleic copolymers were proved to form chelates with platinum-containing anticancer drugs (cis-diamminedichloroplatinum(II), trans-l,2-diaminocyclohexane platinum) through a monocarboxylato and a 0->Pt coordination linkage. These complexes self-assembled into nanoparticles with an increased in-vivo tumors inhibition due to their internalization into the cancer cells. The release of the platinum-containing drug was pH dependent [211,212]. 

Many complexes and coordination compounds exist as isomers, compounds that contain the same numbers of the same atoms but in different arrangements. For example, the ions shown in (13a) and (13b) differ only in the positions of the Cl ligands, but they are distinct species, because they have different physical and chemical properties. Isomerism is of more than academic interest for example, anticancer drugs based on complexes of platinum are active only if they are the correct isomer. The complex needs to have a particular shape to interact with DNA molecules. 

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) ... 

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. 

Rosenberg, B. Platinum Complexes for the Treatment of Cancer. Why the Search goes on. In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Wiley-VCH New York, 1999 pp 3-30. 

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. 

In 1965 Rosenberg et al. (8, 9) accidentally discovered the antiproliferative effect of cis-diammine platinum complexes, which led to the first clinical trials of cis-[PtCl2(NH3)2] 1 in 1971 and resulted in the clinical use of cisplatin worldwide. Cisplatin and carboplatin 2 are the most widely used anticancer drugs, and two other analogs, nedaplatin 3 and oxaliplatin 4 (chiral centers indicated), have recently been approved for clinical use in Japan and France, respectively. 

The early empirical structure-activity relationships promoted discovery of second-generation anticancer drugs such as complexes 2 and 3. However, analogs of these drugs usually display similar clinical profiles to the parent drugs. Therefore new classes of platinum complexes are required with distinct properties. 

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. 

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