Structure Selective mRNA Recognition for HIV-1 RRE: New routes towards synthesis of 2-deoxystreptamine analogue -the central scaffold of Aminoglycosides.

Abstract

Most of the drugs till date aim to bind proteins which are difficult macromolecular targets. RNA finds various roles within organisms including storage of genetic information as in case of hepatitis virus, messenger and transfer RNA are involved in protein synthesis, while snRNA is responsible for splicing. Hence, there are a number of RNAs that are biologically viable therapeutic drug targets and in our project we are particularly interested in the mRNA of HIV-retrovirus. Many cellular processes are regulated by the specific interaction of a protein alpha-helix with a specific region of the DNA or RNA. Neomycin, an aminoglycoside antibiotic, shows micro-molar binding to the Rev Response Element (RRE) of HIV-1 mRNA. 2-deoxystreptamine, the Ring B of neamine is a common scaffold for many aminoglycosides. This work describes the synthesis of 2,5-dideoxystreptamine, a molecule of intermediate complexity that retains four of the heteroatom substituents and preserves the stereochemistry of 2-DOS. The traditional bisepoxide route to the molecule has been performed via bis-epoxidation, followed by ring opening of the cis epoxide with hydrazine and subsequent reductive cleavage, in order to understand the loopholes of the method. New routes towards this central scaffold were sought due to the low yielding epoxidation step involved in the synthetic route discussed above. This piece of work brings forth three novel strategies towards the synthesis of the 2,5-dideoxystreptamine analogues from nitro based compounds. Strategy A starts with cross metathesis between nitro-olefins and alkenals followed by intramolecular nitroaldol to give cyclic nitroalcohol containing a double bond that can suitably be substituted to append a library of 2, 5-dideoxystreptamine analogues Strategies B and C are based on reaction of various nitro alkenes synthesized in the lab to yield nitroalcohols either via Henry's Nitroaldol Reaction or tin (II) chloride mediated reaction with bromonitromethane. These nitroalcohols are subsequently alkylated by alkenes followed by ring closing metathesis to yield 2,5-dideoxystreptamine analogues. Ground research for these new techniques have been performed in this thesis and improvement in the various reaction conditions and procedures of these strategies may provide high yielding routes to the synthesis of these 2,5- dideoxystreptamine analogues.

Date of Award	1 Aug 2013
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Berrisford (Supervisor)