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Design and synthesis of novel sulphur containing anthracene-9,10-diones. / Patrick Joseph Furlong

Swansea University Author: Patrick Joseph Furlong

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 suffer containing anthracene-9,10-diones have been researched for their biological activity, a...

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Published: 2003
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42568
first_indexed 2018-08-02T18:55:01Z
last_indexed 2018-08-03T10:10:30Z
id cronfa42568
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spelling 2018-08-02T16:24:29.6965988 v2 42568 2018-08-02 Design and synthesis of novel sulphur containing anthracene-9,10-diones. acdfae97920c64ebc65c083482644a0e NULL Patrick Joseph Furlong Patrick Joseph Furlong true true 2018-08-02 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 suffer 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-diones were synthesized, seventeen of which have not been previously reported. Twelve of those derivatives contained suffer 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 l-(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 AMI, 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 AMI method was selected to model the synthesized anthracene-9,10-dione derivatives in this work. AMI produced more accurate results for the nitrogen-carbon and oxygen carbon bond lengths. It also required no constraints when the simple suffer derivatives were optimised. A series of reference calculations at the ab initio 6-3IG** level were also carried out, to check veracity of the 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. E-Thesis Organic chemistry.;Pharmacology. 31 12 2003 2003-12-31 COLLEGE NANME Chemistry COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-02T16:24:29.6965988 2018-08-02T16:24:29.6965988 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Patrick Joseph Furlong NULL 1 0042568-02082018162504.pdf 10805317.pdf 2018-08-02T16:25:04.7370000 Output 10592591 application/pdf E-Thesis true 2018-08-02T16:25:04.7370000 false
title Design and synthesis of novel sulphur containing anthracene-9,10-diones.
spellingShingle Design and synthesis of novel sulphur containing anthracene-9,10-diones.
Patrick Joseph Furlong
title_short Design and synthesis of novel sulphur containing anthracene-9,10-diones.
title_full Design and synthesis of novel sulphur containing anthracene-9,10-diones.
title_fullStr Design and synthesis of novel sulphur containing anthracene-9,10-diones.
title_full_unstemmed Design and synthesis of novel sulphur containing anthracene-9,10-diones.
title_sort Design and synthesis of novel sulphur containing anthracene-9,10-diones.
author_id_str_mv acdfae97920c64ebc65c083482644a0e
author_id_fullname_str_mv acdfae97920c64ebc65c083482644a0e_***_Patrick Joseph Furlong
author Patrick Joseph Furlong
author2 Patrick Joseph Furlong
format E-Thesis
publishDate 2003
institution Swansea University
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
active_str 0
description 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 suffer 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-diones were synthesized, seventeen of which have not been previously reported. Twelve of those derivatives contained suffer 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 l-(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 AMI, 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 AMI method was selected to model the synthesized anthracene-9,10-dione derivatives in this work. AMI produced more accurate results for the nitrogen-carbon and oxygen carbon bond lengths. It also required no constraints when the simple suffer derivatives were optimised. A series of reference calculations at the ab initio 6-3IG** level were also carried out, to check veracity of the 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.
published_date 2003-12-31T10:24:54Z
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score 11.055006

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