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Thesis of Novel Anticancer Agents with Therapeutic Potential University of Bath PHD The synthesis of novel anticancer agents with therapeutic potential Ganeshapillai, Dharshini Award date: 2001 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 08. Oct. 2021 THE SYNTHESIS OF NOVEL ANTICANCER AGENTS WITH THERAPEUTIC POTENTIAL Submitted by Dharshini Ganeshapillai for the degree of Doctor of Philosophy of the University of Bath 2001 COPYRIGHT Attention is drawn to the fact that the copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purpose of consultation. UMI Number: U601685 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U601685 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 r nBDSM Bscrr” ~"S!7Y OF 6 V, LBRARY M3 - 8 MAY 2092 Pk,TX _____ I For the loving memory of my dad to my mum for her endless love and devotion Abstract Inhibition of steroid sulphatase activity is an important target for the development of new drugs for oncology and immunology. In this work, synthetic procedures to synthesise novel, potent non-steroidal, non-estrogenic sulphamate derivatives for the treatment of postmenopausal women with hormone dependent breast cancer, and 2- substituted estrone-3-sulphamide, 3-sulphonamide and 3-S-sulphamate derivatives as potential antitubulin, antiangiogenic and apoptotic inducers are described. The strategies adopted to develop STS inhibitors are to develop compounds which are active in vivo and devoid of any estrogenicity, an unwanted property that would limit their clinical use such as the potent estrone-3-O-sulphamate (EMATE). Structure- activity studies were carried out on the lead 4-methylcoumarin-7-0-sulphamate (COUMATE) by incorporating longer alkyl chains and other functionalities at the C-4 and/or C-3 positions of the coumarin ring. Also, a fused third ring was incorporated to give tricyclic coumarin sulphamates, which structurally might mimic the ABCD rings of the steroid. Similar to coumarin sulphamates other heterocyclic ring containing sulphamates are also of considerable interest. Therefore, several novel 1, 2, and/or 3- substituted indole sulphamates were also syntheisesd. The best inhibitors in the C-3 and C-4 alkyl series were those with 7-9 and 6-9 carbon- containing alkyl chains at the C-3 or C-4 positions, respectively inhibiting the El-STS activity in MCF-7 cells at 0.01 juM by 85-91% and >90%. (c.f. 35% for COUMATE). The 3-benzyl-4-methylcoumarin-7-Osulphamate (95) was found to be a potent inhibitor with an IC50 of 8 nM. In the tricyclic coumarin-based analogues with a third ring of sizes between 5 and 15 carbons (665-6615 COUMATES), more powerful active site-directed inhibitors than EMATE and its analogues were found. The most potent compounds in this series, 669 COUMATE (119) and 6610 COUMATE (122) have ICso’s of 2.4 and 1 nM, respectively in vitro and are non-estrogenic in vivo. Interestingly, 6615 COUMATE (131) proved to be the most active congener in vivo. The higher potencies observed for the alkyl series of compounds can be due to their bicyclic system mimicking the A/B rings of steroid backbone with their C-3 or C-4 alkyl substituents interacting with the amino acid residues at the active site, which normally recognise the C/D rings of steroid. The higher inhibition observed for the tricyclic COUMATEs could be attributed to the fact that the third cyclic rings might fold in such a way to mimic the C/D ring conformation of the steroid and hence have better recognition for binding at the enzyme active site. In addition, the lipophilicity of the tricyclic compounds was studied by calculating the log P values by an HPLC technique and the X-ray crystal structures of compounds 119 and 122 were determined. 2-Methoxyestradiol, a natural estradiol metabolite, is non-estrogenic, known to induce G2/M phase cell cycle arrest and apoptosis. The sulphamate derivatives of this compound, 2-MeO/2-EthylEMATE and 2-MeO/2-EtE2MATE have previously been found to be more potent, irreversible and non-estrogenic inhibitors, and also shown to trigger apoptosis and inhibit tubulin polymerisation. It is therefore possible that the structurally similar derivatives of these synthetic sulphamates, such as the 2-substituted 3-sulphamide, 3-sulphonamide and 3-S-sulphamate, with nitrogen or sulphur bridging heteroatoms at the C-3 position would also inhibit tubulin polymerisation and angiogenesis. These compounds would provide an indication about the importance of the sulphamoyloxy group for potent activity in 2-MeOEMATE, which is thought to elicit effect by taken up into blood cells and released slowly. Therefore, presumably acting as a pro drug of 2-MeOEl. There are certain sulphonamides, which are known to bind to carbonic anhydrase in the blood cells therefore the sulphonamides syntheised might also show similar inhibitory activities to that of the sulphamates. Most importantly, these compounds would offer useful information about the site where the sulphamoyl group binds in tubulin and the mechanism of binding for irreversible inhibition, which might be similar to that of sulphamoylation of sulphatase enzyme. This structure-activity study would also show how the stability of the sulphamoyloxy group could be improved further. Therefore, novel sulphamate surrogates such as 2- methoxy and 2-ethyl 3-sulphamide, 3-sulphonamide and 3-^-sulphamates are synthesised in this work and their synthetic methods are reported. Acknowledgements I would like to express my gratitude to my supervisor, Professor B. V. L. Potter for giving me an opportunity to work on this project and for his inspiring guidance and enthusiasm through out this project. My heartfelt thanks to Dr. Lawrence Woo for all the encouragement and his patience in reading my thesis. My sincere thanks to Dr. Mike Threadgill for his generous support and helpful advice throughout the course of this work. I wish to extend my appreciation to Professor Mike Reed and Dr. Atul Purohit at the Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St. Mary’s Hospital, London for the biological evaluation of all my compounds, for their helpful suggestion and friendship. My sincere thanks to Dr. Mary Mahon at the Department of Chemistry, University of Bath, for X-ray crystallography and Mr. Kevin Smith for molecular modelling of my compounds. Special thanks are also to all the technical staff at the University of Bath for NMR, mass spectral and microanalysis services. I would like to thank all my friends in the department, especially Hatem, Ifat and Jackie for their friendship and encouragement and for all the fun. My thanks are also due to Sarah Al-Benna and Shabhano Ali for being good friends and for their moral support. Finally, I am indebted to my mum for all her love, encouragement and endless support throughout my life and she is the best mum in the world. I would like to thank Suthan for his love, encouragement and being very understanding, tolerant and supportive all the way. My sincere thanks to my sisters, family and friends for their encouragement and support. Publications Some of the work described in this thesis have been published in the following publications or in preparation: B. Malini, A. Purohit, D. Ganeshapillai, L. W. L. Woo, B. V. L. Potter, M. J. Reed. Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamates; Journal o f Steroid Biochemistry and Molecular Biology, 2000, 75, 4-5, 253-258. D. Ganeshapillai, L. W. L. Woo, M. J. Reed, B. V. L. Potter. Tricyclic coumarin sulphamates : potent, non-steroidal inhibitors of estrone sulphatase; (2001), Manuscript in preparation. D. Ganeshapillai, L. W. L. Woo, M. J. Reed, B. V. L. Potter. Substituted coumarin sulphamates : potent, non-steroidal inhibitors of estrone sulphatase; (2001), Manuscript in preparation. D. Ganeshapillai, L. W. L. Woo, M. F. Mahon, M. J. Reed, B. V. L. Potter. X-ray crystal structural analysis of the tricyclic coumarin sulphamates; (2001), Manuscript in preparation.
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