Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.637016
Title: Design and synthesis of novel sulfur containing anthracene-9,10-diones
Author: Furlong, P. J.
Awarding Body: University of Wales Swansea
Current Institution: Swansea University
Date of Award: 2004
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Abstract:
It is well established that certain anthracene-9,10-diones such as Mitoxantrone (24b) and Amentantrone (24a) are potent anticancer drugs but suffer from the disadvantage that they are also cardiotoxic. Few sulfur containing anthracene-9,10-diones have been researched for their biological activity, and the current studies were aimed to synthesise a series of anthracene-9,10-dione derivatives containing both as substituted and as part of the ring system in an endeavour to conserve their anticancer activity but reduce their cardiotoxicity. A series of twenty four anthracene-9,10-dione were synthesized, seventeen of which have not been previously reported. Twelve of those derivatives contained sulfur and include the 1,4-bis(amino)-5,8-bis(sulfanyl)anthracene-9,10-diones, which were synthesised from the amination of 2,3-dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione with selected amines followed by the subsequent reaction with thiolates. A ring derivative was also synthesised, 7-(aminoalkyl)-14H-naptho[2,3-a]phenothiazine-8,13-dione from the reaction of 1-(alkylamino)-4-hydroxyanthracene-9,10-dione and 2-aminothiophenol with boric acid. Semi-empirical molecular orbital methods were employed to model the anthracene-9,10-dione derivatives. To establish the most appropriate method for calculation a set of well known anthracene-9,10-diones were selected from the Cambridge crystallographic database and compared to computational data obtained using the AM1, PM3 and MNDO methods. All three methods give reasonable structures by comparison with the experimental data, when suitable constraints were applied to the optimisations. On balance the AM1 method was selected to model the synthesized anthracene-9,10-dione derivatives in this work. AM1 produced more accurate results for the nitrogen-carbon and oxygen carbon bond lengths. It also required no constraints when the simple sulfur derivatives were optimised. A series of reference calculations at the ab initio 6-13G** level were also carried out, to check veracity of the results obtained form the AMI method. The computational data highlighted two factors that may be significant in the biological activity of anthracene-9,10-diones. It appears that molecules that are biologically active contain alkylamino groups at the 1-and 4- position and have ionization potentials in the range of 7.7-7.9 eV. The computational data of the derivatives synthesized in this work shows many of them meet this criteria and therefore may possess anti-cancer activity, though this aspect of the research was not addressed in the current studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.637016  DOI: Not available
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