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Synthesis of 8-alkylthioguanineas GTP cyclohydrolase (I) inhibitors for the treatment of cancer pain. Towards amino acids: asymmetric [1,2]-Stevens rearrangements and [2,3]-sigmatropic rearrangements.

Akriem, Hamad A. M. (2018) Synthesis of 8-alkylthioguanineas GTP cyclohydrolase (I) inhibitors for the treatment of cancer pain. Towards amino acids: asymmetric [1,2]-Stevens rearrangements and [2,3]-sigmatropic rearrangements. Doctoral thesis, University of Huddersfield.

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Abstract

Pain is a major symptom of patients with advanced cancer. Tetrahydrobiopterin (BH4) has been found to be a key modulator of cancer pain. Two enzymes GTP cyclohydrolase I (EC 3.5.4.16; GTPCH1) and sepiapterin reductase (EC 1.1.1.153; SR) are required for the biosynthesis of BH4. This link between BH4 synthesis and pain provides a new approach for treating neuropathic and other forms of chronic pain. GTPCH1 and SPR enzymes are drug targets based on active site characterization of these two enzymes. Therefore, we wish to develop inhibitors of GTPCH1, SPR key enzymes in the synthesis of BH4 that could potentially be targeted in the treatment of cancer pain. Our work will be focused on the inhibition of GTPCH1 by thiopurines. 8-(alkylthio) guanine and an extensive range of 8-(substituted benzyl thio) guanines were synthesised using traditional reactions of purine chemistry in 13-98% yields. The target compounds are accessible from readily available nucleosides.

This part of thesis describes research towards the synthesis of amino acids via[1,2]-Stevens rearrangements of benzylic ammonium ylids and [2,3]-sigmatropic rearrangements of allylic heteroatoms. Firstly, [1,2]-Stevens rearrangements using camphorsultam as the chiral auxiliary, it was found that yields were improved when BTPP, 5 Åmolecular serves and DMSO as solvent were used. We have reported 12 examples of [1,2]-Stevens rearrangement of benzylic ammonium ylids with different benzyl substituted(61-89% total yields) as well as three examples of non-coded amino acids(32-39%).Finally, we have reported the metal catalysed [2,3]-sigmatropic rearrangementsof allylic heteroatoms (N,I,S).The investigation was done viausing diazo attached to a chiral auxiliary (camphorsultam and benzyl oxazolidinone), allyl heteroatoms and catalysts (5,10,15,20-Tetrakis(pentafluorophenyl)-21H, 23H-porphyrin iron(III) chloride and rhodium(II) acetate). Reactions of the diazo oxazolidinone and the diazo chiral benzyl oxazolidinone worked well with highly reactive iron(III) porphyrin catalyst in the presence of the N,N dimethylallylamine and gave high yields (70%, 86% respectively), although diastereoselectivity was poor (1:1.5). Rhodium(II) acetate catalysed decomposition of the diazoaceyl camphorsultam in the presence of the ally iodide and produced high yield (>90%) and excellent diastereoselectivity (5.6:1).

Item Type: Thesis (Doctoral)
Subjects: Q Science > QR Microbiology
R Medicine > RM Therapeutics. Pharmacology
Schools: School of Applied Sciences
Depositing User: Rebecca Hill
Date Deposited: 03 Jan 2019 17:07
Last Modified: 07 Feb 2019 15:31
URI: http://eprints.hud.ac.uk/id/eprint/34798

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