Synthesis of Complex Sugar Mycolates of Mycobacterium Tuberculosis

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  • Omar Ali

Abstract

Mycobacteria are present in many environments and complex mixtures of sugar esters and mycolic acids are present in their cell wall structure. This complicated mixture is thought to be responsible for their high resistance to known antibiotics and chemotherapeutic treatments. Mycolic acids are high molecular weight α-alkyl-branched β-hydroxy long-chain fatty acids, have 60-90 carbon atoms, and various classes of mycolic acids are made by different species of mycobacteria. Sugar esters of mycolic acids associated with the cell wall of mycobacteria have very interesting toxic and immunological properties, and thus could be useful for the control and treatment of mycobacterial infections. The main objectives of this thesis will be discussed in three parts. The main target of the first part involved the first synthesis of a single enantiomer of the glycolipid di-mycolyl di-arabino glycerol (DMAG) (I), which has interesting toxicological and immunological properties. This was achieved by a successful synthesis of the glycan moiety of DMAG with the L-stereochemistry of the glycerol component, followed by the successful esterification of the glycan di-arabino glycerol with three normal fatty acids, a model mycolic acid, and five different mycolic acids. The NMR spectra of the synthetic isomer of the DMAG penta-acetate analogue, in the sugar region, matched very well those reported for the peracetate formed from the natural mixtures, confirming the stereochemistry of the arabinose units and establishing the absolute stereochemistry of the glycerol unit. An efficient route to prepare the DMAG glycan with excellent β-selectivity and in excellent yield was achieved. The second part entailed the first preparation of di-mycolyl tri-arabino glycerol (DMTAG) (II), which involved the synthesis of the donor moiety part according to literature methods with slight modifications, and the new arabino glycerol acceptor. The coupling of the donor and the acceptor to prepare the desired glycan was carried out using known coupling conditions. After the success in synthesising this tetra-saccharide, a model glycolipid was prepared through esterification with a normal fatty acid. Furthermore, a series of three DMTAG compounds were prepared, based on two common classes of mycolic acids. The final part of this project was the synthesis of glycerol mycolates (GroMM) (III), which have interesting adjuvant properties in vaccines, by coupling five common classes of synthetic mycolic acids with the S-glycerol stereoisomer. One model GroMM was prepared from a simple fatty acid. These compounds were prepared to study whether the stereochemistry of the glycerol component (R & S) has any effect on their biological activities. Initial studies of the biological activity of the synthetic DMAGs showed that some could be used to distinguish serum from cattle infected with bovine TB from uninfected cattle, and that they selectively activate THP-1 cells. In contrast, initial ELISA results with the synthetic GroMM showed little response to serum from patients with active TB.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • Mark Baird (Supervisor)
  • Juma'a Al-Dulayymi (Supervisor)
Thesis sponsors
  • Iraqi Ministry of Higher Education and scientific research
Award dateJan 2017