Platinum-based anticancer drugs

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. 

Dhar, S. Lippard, S. J. Current Status and Mechanism of Action of Platinum-Based Anticancer Drugs. In Bioinorg. Med. Chem. 79-95 (Wiley-VCH Verlag) (2011). 

O Dwyer, P. J. Stevenson, J. P. Johnson, S. W. Clinical Status of Cisplatin, Carboplatin, and Other Platinum-based Antitumor Drugs. In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Wiley-VCH New York 1999, pp 31-72. 

Farrell, N. P. Polynuclear Charged Platinum Compounds as a New Class of Anticancer Agents Toward a New Paradigm In Platinum-Based Drugs in Cancer Therapy, Kelland, L. R. and Farrell, N. P., Ed. Humana Press, 2000, pp 321-338. 

In our group, a major part of our research is devoted to the design of new anticancer drugs. Our recent efforts towards the discovery of new platinum-, ruthenium- and osmium-based anticancer agents provide the topic for this account and a section is devoted to each metal. We focus on recent results from our lab in the context of other developments and related research in this field (hence our coverage of the field is focused on these areas and is not comprehensive). 

Fig. 1. Molecular structures of (a) some platinum(II)-based anticancer drugs currently used in the clinic (b) satraplatin, a platinum(IV) prodrug currently in clinical trials.

In the process of identifying the reaction products of the anticancer drug cis-DDP with DNA bases, unusually dark blue compounds were found, which were called platinum-pyrimidine-blues. Interestingly,... 

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. 

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]. 

There have been numerous studies of the interaction of the highly effective anticancer drug cisplatin, c/5-[Pt(NH3)2Cl2], with DNA. The majority of these studies have concentrated on the adduct formed between the platinum(II) ion and two adjacent guanine bases (G) on one strand of DNA this is the adduct most frequently... 

The scientists quickly realized that cisplatin could be a useful drug against some kinds of cancer, where cells often divide in abnormal ways. Their studies led to a number of platinum-based anticancer drugs, including cisplatin, which are still used to fight tumors. 

Chemotherapy refers to drug administration with highly serious side effects, such as nausea, hand and foot rashes, mouth sores, and increased risk of infection, easy bruising, and so on. Therefore, liposomal carriers have been used in order to improve the drug s biodistribution and protect the patient from those side effects. The main anticancer drugs used to treat ovarian cancer are carboplatin and cisplatin, paclitaxel, topotecan, and lurtotecan. PEGylated liposomal doxorubicin has been approved as a regimen for patients with metastatic ovarian cancer refractory to both paclitaxel and platinum based-therapy [449],... 

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. ... 

Topics not included here or appearing in more length elsewhere include book-length discussions of concepts and summaries,toxic metal ions in the environment and nervous system, " and cisplatin as an anticancer agent (see Platinum-based Anticancer Drugs). An element by element discussion of toxicity appears in a convenient handbook. ... 

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