Azathioprine, AZA, a slow release prodrug of 6-mercaptopurine, 6MP, is an established clinical agent for the treatment of human lukemias'. Along with its anti-tumor activity AZA is also widely used as an immunosuppressant in the prevention of rejection of various transplanted organs as well as an anti-inflammatory agent in the treatment of rheumatoid arthritis. Apart from it's biological significance, the coordination chemistry of AZA with metals is also significant because the molecule offers a number of versatile binding sites which are potentially capable of coordinating with metals. Preliminary studies on a number of these AZA- metal complex have established them as possessing anti-tumor activity, in some cases greater than that of the parent molecule. This study is aimed at understanding the selective binding properties of Aza, 6mp, their complexes and analogues, with the intent of clarifying the link between the drug's chemotherapeutic activity and its coordination chemistry. The factors affecting the choice of binding sites involved in the binding of AZA, 6MP, their complexes and analogues with a silver surface will be investigated using surface-enhanced Raman spectroscopy, while the interaction between AZA-metal complexes and DNA will be investigated using absorption spectroscopy and surface-enhanced Raman spectroscopy. The proposed study will correlate the effect of binding site electronegativity and stereochemical constraints, on the mode of interaction of AZA and its metal complexes with a ilver surface and also with DNA. This study will expand on the existing knowledge on drug metal interactions, a knowledge of which is important in understanding the factors affecting in vivo metal transport. These interactions have been shown to be important considerations in the development of slow release or long acting drugs. Elucidation of the mode of interaction of md AZA-metal complexes and DNA will identify the molecular parameters which are responsible for the drug's two main chemotherapeutic features, its cytotoxicity and inhibition of cellular proliferation. Establishment of a correlation between the drug's molecular structure and its cytotoxicity would be instrumental in the design and synthesis of new drugs possessing reduced cytotoxicity.
| Chen, Shi-Ping; Qiao, Zhuahong; Vivoni, Alberto et al. (2003) Determination of the orientation of azathioprine adsorbed on a silver electrode by SERS and ab initio calculations. Spectrochim Acta A Mol Biomol Spectrosc 59:2905-14 |
