Design, synthesis and evaluation of spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics
Nature contains an endless supply of natural products and has for long been a source of inspiration for the pharmaceutical industry. Many of the drugs currently in clinical use originate from natural products. Paclitaxel, the active substance in the anti cancer medicine Taxol, was first isolated from the Pacific yew tree (Taxus brevifolia) in the early 1960s during a screening program for novel anti cancer agents, initiated by NCI. After the discovery of paclitaxel’s unique mechanism of action as a microtubule stabilizer, intense research followed, which despite drawbacks such as supply problems and low water solubility, resulted in the successful anti cancer medicine Taxol. At present, Taxol is used in the treatment of ovarian, breast and non-small cell lung cancer. The primary intention with the work presented in this thesis was to design and synthesize paclitaxel mimetics, based on a rigid skeleton decorated with the groups important for the paclitaxel activity. Molecular modelling was used to identify a spiro-bicyclo[2.2.2]octane skeleton as a suitable substitute for the rigid paclitaxel core. Four different paclitaxel mimetics have successfully been synthesized and tested for their biological activity in five breast-derived cell lines. In addition, some intermediates were also included in the biological evaluation. Some of the compounds tested were shown to be toxic but were less active than paclitaxel itself. In addition, methodology for the synthesis of bridgehead substituted bicyclo[2.2.2]octane-2,6-diones were developed followed by evaluation of the products as substrates in the asymmetric baker’s yeast reduction.
Source Type:Doctoral Dissertation
Keywords:NATURAL SCIENCES; Chemistry; paclitaxel; asymmetric baker's yeast reduction; spiro; bicyclo[2.2.2]octane; paclitaxel mimetics
Date of Publication:01/01/2008