Our studies on the synthesis and biological evaluation of novel anticancer drugs consist of three research areas; namely, synthesis of Mitogen Activated Protein (MAP) kinase inhibitors, Checkpoint (Chk1) inhibitors and nordihydroguaiaretic acid (NDGA) analogues. The first research area involved synthesis of MAP kinase inhibitors. MAP kinases are a family of serine I and threonine II kinases which can act together to generate a process of phosphorylation events within the cell signalling pathway leading eventually to cell division. The compounds made in this project were specifically designed to target the stress related kinases, a MAP kinase pathway which controls the expression of genes involved in cell proliferation. The stress related kinases are known to have serine or threonine joined to a proline III residue. In an attempt to prepare selective inhibitors of stress related kinases, compounds of types IV and V were deigned in which a conformationally restricted serine analogue is joined to L-proline via an amide link in one of two possible ways. Examples of these two sets of compounds were synthesised and those that were tested by Professor David Gillespie at the Beatson Institute for Cancer Research, Glasgow were shown not to be inhibitors of these kinases. (Fig. 1144A) The second research area concentrated on the checkpoint signalling pathway. Components in the DNA damage checkpoint signalling pathway such as ChK1 could be potential targets for chemical intervention. Caffeine VI and pentoxifylline VII have been shown to sensitise p53-deficient tumour cells to killing by DNA damage. We envisaged that the xanthine derivatives, caffeine VI and pentoxifylline VII might also disrupt the G2 checkpoint by preventing activation of Chk1. To test his hypothesis, a range of xanthine derivatives shown below were prepared by alkylation of theophylline VIII or theobromine IX. (Fig. 1144B) The biological evaluation of these xanthine derivatives by Professor Gillespie revealed that three of these compounds, X, XI and XII, suppressed G2/M arrest very effectively. All three active compounds possess a long aliphatic chain that provides a large degree of flexibility to the structures. The long aliphatic chains could bind to a hydrophobic pocket in the enzyme’s active site that might confer selectivity on the compounds. (Fig. 1144C) The third area, synthesis of NDGA analogues, was the major part of the synthetic work. NDGA XIII is known to be a selective inhibitor of lipoxygenase and blocks small cell lung cancer growth in vitro and in vivo. In addition to its lipoxygenase activity, NDGA was demonstrated to inhibit c-kit, a tyrosine kinase that has been observed preferentially in SCLC. The main drawbacks to the use of NDGA in cancer treatment are its poor solubility and moderate potency. Therefore chemical modifications are required to provide better compounds for clinical use. Preliminary work in our group was performed by McDonald and Macleod. They synthesised a range of analogues of NDGA which were tested for their activity in vitro by Professor Michael Seckl at the Medical Oncology Department of Hammersmith Hospital, London. Improved potency over NDGA for new analogues with 4-6 atoms between the two aromatic rings was observed. Furthermore introduction of an amide linkage between the two aromatic residues resulted in NDGA analogues which are more active than NDGA. Based on these preliminary results, the structural modifications proposed for this project focused on three areas. The main programme of research was drug solubilisation of new analogues which have higher potency than NDGA for in vivo work. The second area of study sought to introduce position variations of the amide linkage between the two aromatic residues. The third area of work involved modification of the substituents on the two aromatic rings. (Fig. 1144D) A range of NDGA analogues was successfully synthesised and evaluated for anticancer activity in vitro. Compounds XIV and XV were confirmed as lead compounds which are ten times more active than NDGA. Compound XIV was successfully transformed into a water soluble form XVI which is now available for in vivo work. In addition NDGA was converted into a water soluble form which was more potent than NDGA in vitro. Moreover a NDGA analogue XVII with no free hydroxy groups was found to be as active as NDGA, which was an unexpected discovery. (Fig. 1144E)
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:404501 |
| Date | January 2003 |
| Creators | Liu, Tong |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/4464/ |
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