Studies Towards the Development of a Novel Anti-Cancer Agent

This project has been a collaborative effort involving the design, synthesis and testing of analogues of the fungal metabolites viridin, demethoxyviridin and wortmannin. Extraction methods of viridin, from Trichoderma viride were developed and initially provided a lead compound for testing. Data relating to the anti-inflammatory activity of wortmannin analogues was available in the literature and was used in a computer modelling program SYBYL to build a structure activity relationship from which activity of new analogues could be predicted. The crystal structure determination of demethoxyviridin provided detailed structural information about these molecules. This was used in modelling studies to guide the synthesis of new compounds, leading to the synthesis of an analogue several hundred times more active than the original lead compound. A patent has been applied for this compound and it is presently being forwarded for cinical trials in animals for toxicity testing. The compounds were shown to be cytotoxic in vitro and inhibit specific enzymes in the signal transduction pathway. Preferential inhibition of mitogen stimulated cells was shown, indicating that some degree of selectivity was built into the molecules, suggesting that future compounds may have relatively few side effects due to their novel mechanism of action