Anti-Tumour Activity of Platinum Complexes

It has been found that certain features are desirable, if not essential, in active platinum complexes  

Two ammine groups (with at least one H per N) in a m-configuration (or a bidentate ammine) 

The presence of good leaving groups like chloride or carboxylate in a cis-configuration 

Palladium(II) complexes with these features are inactive, owing to their greater lability. Platinum(IV) complexes are often less toxic than their platinum(II) analogues, because of their stability to substitution, though it is believed that they undergo in vivo reduction to platinum(II). 

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204], 

Loss of Cl- makes the platinum complex more reactive, since water is better leaving group than Cl-. 

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A resurgence of interest in these seemingly simple complexes of platinum started in 1969 when B. Rosenberg and co-workers discovered the anti-tumour activity of cis-[PtCl2(NH3)2]... 

Roos IA, Arnold M. Interaction of an anti-tumour active platinum complex with DNA. J ClinHematol... 

Platinum coordination complexes have been investigated as potential anticancer agents since 1972. The most successful of these is the cis dichlor-diammine platinum(II) complex which is particularly effective for the treatment of ovarian and testicular carcinomas. However, effective therapy requires high doses, typically 4.0/umol (825/ig)kg-1 given intravenously, which produce unpleasant and toxic reactions. Pharmaco-kinetic studies of the various Pt species in plasma indicate that the active species is of low molecular weight and the protein bound Pt species is apparently inactive [106]. Further work is needed to identify the active species and to develop therapeutic procedures that produce maximum anti-tumour activity with minimum toxicity. 

There has been considerable interest in recent years in the formation of condensed films of purine and pyrimidine bases at the solid-liquid interface. It is well recognised that non-covalent affinities between base pairs play a prevalent role in determining nucleic acid conformation and functionality. Likewise, there has been interest in the role of substrate and non-covalent intermolecular interactions in the configuration of ordered monolayers of purine and pyrimidine bases. There is also more general interest in the interaction of bases with metal surfaces and metal complexes. In the latter case it is noted that the biological role of nucleic acids and certain nucleotides are dependent on metal ions, particularly Mg, Ca, Zn, Mn, Cu and Ni. " Also certain metal complexes, notably of platinum, have the anti-tumour activity, which is linked to their ability to bind to bases on DNA. On a different note, the possibility that purine-pyrimidine arrays assembled on naturally occurring mineral surfaces might act as possible templates for biomolecular assembly has been discussed by Sowerby et al. 

Platinum co-ordination complexes share the common formula PtA2X2 with only the a s-isomers displaying an anti-tumour activity. The active X ligands are monodentate anions of intermediate leaving ability, whereas the amine A ligands influence... 

Anti-tumour chemotherapeutic agents, doxorubicin and (dach)platinum(II) complex (where dach is trans-1,2-diaminocyclohexane) were introdueed into poly(organophosphazene) using L-glutamic acid as a spacer. The in vivo anti-tumour activity increased with increasing (dach)platinum(II) content, the conjugate containing 12.3 mol% of doxorubicin and 47.6 mol%... 

Table 3. The effect of different classes of anti-tumour agent on some transplanted tumours. The TLX5 (R) is a line with acquired resistance to a triazene and is cross resistant to BCNU. Triazenes and BCNU are active against tumours which do not respond to anti-metabolites and others that are insensitive to alkylating agents. The platinum complex was cis dichloro-bis(cyclopentylamine)platinum(II) and the triazene 5-(3,3-dimethyl-l-triazeno)-4-carbethoxy-2-me thy limidazole...

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