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| Palladium Catalysed Multicomponent Reactions Generating Gene Off/On Switches: Treating Endometrial Cancer. | ||||||||||||
The project is focused on computer based design and chemical synthesis of histone deacetylase inhibitors (HDACi) which are promising novel anti-cancer drugs that function by switching on genes that control the destruction of cancer cells. There is a group of eleven such enzymes which target a range of different types of cancer. HDAC 2 and HDAC 3 are the important targets for endometrial and ovarian cancers. The student will be trained to use our established drug design computer software to identify promising drug candidates by in silico docking of the designed drugs into the enzyme active site. Application of sieve and scoring functions will then allow the designed drug candidates to be ranked in priority order for synthesis. These will then be synthesised by application of our special in-house palladium catalysed multicomponent cascade reactions. These are reactions whereby multiple different chemical building blocks are loaded into the reaction flask with a palladium catalyst and, by controlled heating, assembled into drug candidates in the designed order with exquisite control of regio and stereochemistry and molecular architecture in a continuous process. The drug candidates will then be screened in cell based assays against HEC-1B, Ishikawa, Ark2 etc and their effects on the cell cycle G0/G1 and GM-phases etc. Most studies to date have largely ignored hyperplasia whilst we plan to probe this by immunohistochemistry. The outcome of the screening results will feed back into the in silico design/synthesis loop to achieve nanomolar active drug candidates. The project provides: (i) In depth training in leading edge drug design. (ii) An opportunity to participate in "green" catalytic cascade chemistry and develop new synthetic methods. (iii) Participation in cell based screening of the novel compounds. (iv) Appreciation of clinical cancer problems and exposure to clinicians trialling new drugs. |
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