Anticancer drugs metal complexes

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

In line with expectations of kinetic inertness for third-row transition metals, little interest has been vested in the development of osmium anticancer drugs, as ligand-exchange rates did not seem favorable on the timescale of cellular processes. Our work, however, shows that the kinetic lability of such complexes can be timed to such extent that anticancer activity comes within range. We have demonstrated how rational chemical design can thus be applied to osmium-arene complexes resulting in specific... 

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]. 

Alessio E, Mestroni G, Bergamo A, Sava G (2004) Ruthenium anticancer drugs. In Sigel H (ed) Metal Complexes in Tumor Diagnosis and as Anticancer Agents. CRC Press, USA, pp 323-351... 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

Another biomedical area of interest in metal complexes concerns various anticancer drugs. Puzo et al. (117) and Theodoropoulos (63) have used FAB to study cisplatin [i.e., cis-Pt(NH3)2Cl2] and its complexes and related compounds. For the 1 2 complex with guanosine, peaks due to the complex less a Cl, or less Cl and HC1, along with their corresponding glycerol adducts were observed. Less clear results were observed for other amino acid complexes (63). Cohen et al. (62) and Costello et al. (64) have used FAB to study the complexes of techni-tium(III) and technitium(I) and -(V), respectively, these compounds... 

---