Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527392
Title: Synthetic approaches to PNA-containing acridine threading intercalators as potential novel HIV-1 integrase inhibitors
Author: Collart, Koenraad M. P.
Awarding Body: Heriot-Watt University
Current Institution: Heriot-Watt University
Date of Award: 2010
Availability of Full Text:
Access through EThOS:
Access through Institution:
Abstract:
The overall objectives of this research were to devise a viable synthetic route to conjugates, in which 9-aminoacridine 4-carboxamide was tethered through its 4- position to peptide nucleic acids (PNAs), and to evaluate their abilities to act as novel inhibitors of HIV-1 integrase (IN). It was reasoned that such compounds could inhibit the process catalysed by IN either directly by binding to the enzyme or indirectly by binding to the proviral DNA substrate through threading intercalation. The first route to these conjugates investigated involved synthesis of the intermediates 9-oxoacridan-4-carboxylic acid and the thyminyl-PNA monomer ethyl ester. Both these compounds were successfully prepared following established literature procedures. In order to explore the conditions required for coupling 9-oxoacridan-4- carboxylic acid and the thyminyl-PNA monomer ethyl ester, a model study was undertaken involving preparation of the known threading intercalator, 9-amino-DACA. Following literature precedence, 9-oxoacridan-4-carboxylic acid was treated first with excess thionyl chloride to yield 9-chloroacridine-4-carboxyl chloride. Subsequently, this was reacted selectively with N,N-dimethylethylenediamine to give 9-chloro- DACA. Finally, treatment of a phenolic solution of 9-chloro-DACA with gaseous ammonia successfully afforded 9-amino-DACA in a 26% over-all yield. Unfortunately, on applying a similar approach for synthesis of the 9-aminoacridine-4- carboxamide PNA conjugate, none of the desired compound could be identified. In a second alternative strategy a number of alkyl-9-oxoacridan-4-carboxylate precursors (methyl, iso-propyl and t-butyl) were synthesised and subsequently activated, via 9-triazolylation, to allow for substitution in the 9 position with benzyl amine. This resulted in the successful synthesis of the iso-propyl- and t-butyl-9- benzylaminoacridine-4-carboxylate intermediates. Subsequent attempts to generate the 4-carboxyl group in both intermediates, via alkyl-ester cleavage, were only successful via a basic hydrolysis of the iso-propyl ester. Unfortunately, attempts to activate the 4- carboxyl group of the resulting 9-benzylaminoacridine-4carboxylic acid via 4-Nhydroxysuccinimide (NHS) ester formation, to enable subsequent substitution in the 4 position with a PNA monomer, were unsuccessful. The nature of the 9-amino substituent was found to be of importance as it was shown that for 9-anilinoacridine-4- carboxylic acid, NHS activation of the 4-carboxyl was successful and led to synthesis iii of a 9-anilinoacridine-4-carboxamide PNA conjugate. This result prompted us to revise our strategy and led to the synthesis of 9-t-Boc- and 9-Alloc-aminoacridine-4- NHS esters that subsequently both were coupled successfully to a thyminyl-PNA monomer. Subsequent deprotection steps for the 9-Alloc protected PNA-acridine conjugate proved to be cumbersome but fortunately, for the t-Boc protected PNAacridine conjugate t-Boc cleavage with TFA followed by an aqueous basic ethyl ester hydrolysis of the PNA monomer’s C-terminus resulted in completion of a 9-step synthetic route (4% over-all yield) towards the target 9-amino-4-PNA-acridine conjugate, 2-(N-(2-(9-aminoacridine-4-carboxamido)ethyl)-2-(thymin-1-yl)acetamido) acetic acid. The IN inhibitory activities of 9-amino-DACA and one intermediate 9-aminoacridinecontaining compound were evaluated in a cell based antiviral assay. Although their absolute potencies of inhibition were in the micromolar range, their novel scaffold warrants their further investigation as potential anti-IN inhibitors
Supervisor: Howarth, Nicola M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.527392  DOI: Not available
Share: