Tese 27 Ago - Versao final

104 Pages·2012·2.32 MB·Portuguese

Filipa Sameiro de Oliveira

Prenylated xanthone derivatives: Synthesis of structural
analogues of α-mangostin and antitumor activity evaluation

Master Degree in Industrial Pharmaceutical Chemistry 2012
Dissertação do 2º Ciclo de Estudos Conducente ao Grau de Mestre em Química Farmacêutica
Industrial pela Faculdade de Farmácia da Universidade de Coimbra

Trabalho realizado sob a orientação do Professor Doutor Jorge António Ribeiro Salvador, da
Faculdade de Farmácia da Universidade de Coimbra e coorientação da Doutora Raquel Alexandra
Pinto Castanheiro, da Faculdade de Farmácia da Universidade do Porto.
This work was developed in Departamento de Ciências Químicas (Laboratório de Química
Orgânica e Farmacêutica), Faculdade de Farmácia, Universidade do Porto and Centro de Química
Medicinal da Universidade do Porto (CEQUIMED-UP – PEst-OE/SAU/UI4040/2011).
Master Degree Thesis in Industrial Pharmaceutical Chemistry
Faculty of Pharmacy, University of Coimbra

Author: Filipa Sameiro de Oliveira
[email protected]

Title: Prenylated xanthone derivatives: Synthesis of structural analogues of α-mangostin and
antitumor activity evaluation
Publishing year: 2012

FULL REPRODUCTION OF THIS THESIS IS AUTHORIZED ONLY FOR THE PURPOSE OF RESEARCH, BY
MEANS OF A WRITTEN STATEMENT OF THE INTERESTED PART, TO SUCH A COMMITMENT.

Faculdade de Farmácia da Universidade de Coimbra, Setembro de 2012
The results presented in this thesis are part of the following scientific communication:

• Poster communication:
- F. Oliveira, R. Castanheiro, M. Pinto, J. A. R. Salvador; “Prenylated xanthone derivatives: an
inspiration for synthesis of new inhibitors of growth of human tumor cell lines”; “3rd
Portuguese Young Chemists Meeting” – Porto, Portugal, 9-11 May 2012, P 52.
INDEX

Acknowledgements i
Abstract iii
Resumo iv
Abbreviations and Symbols v
Outline of the Thesis vii

I. INTRODUCTION _ 1
1. Xanthones 3
1.1 Prenylated Xanthones 5
1.2 Caged Xanthones 7
2. Activity of Xanthones 8
3. Synthesis of Xanthones 19
4. Synthesis of Prenylated Xanthones 22
4.1. “Classical” Synthetic Methodologies 22
4.1.1. Molecular extension by prenylation of xanthonic scaffold 22
4.1.2. Molecular rigidification by cyclization of prenylated precursors
and/or Claisen rearrangement 23

4.1.3. Different approaches for the synthesis of prenylated xanthones 25

4.2. “Non-classical” Synthetic Methodologies 26

II. AIMS_______________________________________________________35
III. RESULTS AND DISCUSSION______________________________________37
1. Synthesis of xanthone derivatives 38
Part I – Synthesis of 1,3-dihydroxy-5-methoxyxanthone 38
Part II – Synthesis of Prenylated Xanthones 39
2. Structure Elucidation 41
3. Biological Assays 60

IV. EXPERIMENTAL PART_________________________________________ 62
General Methods 63
Part I – Synthesis of 1,3-dihydroxy-5-methoxyxanthone 64
Part II – Synthesis of Prenylated Xanthones under Microwave irradiation 66
Part III - Tumor Cell Growth Assay 69

V. CONCLUSIONS_______________________________________________ 70

REFERENCES 73

ATTACHMENTS 86
INDEX OF FIGURES

FIGURE
1. Xanthonic scaffold and numbering 3
2. Scaffolds containing a g -pyrone moiety 3
3. Main substituents found in prenylated xanthones 5
4. α-mangostin (A), β-mangostin (B) and γ-mangostin (C) 6
5. Examples of caged xanthone with antitumor activity 7
6. Some pharmacological activities of xanthones 8
7. Xanthonol and α-mangostin structures 9
8. DCX and Mangiferin structures 11
9. Psorospermin and DMXAA structures 16
10. Synthesis of xanthones via GSS reaction 19
11. Synthesis of xanthones via benzophenone and via diaryl ethers intermediates 20
12. Xanthone synthesis by Verbanac, D. et al., 2012 21
13. Prenylation of the xanthonic scaffold with different experimental conditions (i, ii) 22
14. Claisen rearrangment of prenylated precursors (i, ii) 23
15. Synthesis of dihydropyranoxanthones 24
16. Synthesis of a -mangostin 25
17. Electromagnetic spectrum 27
18. Dipolar polarization; microwave versus traditional heating process 28
19. MW equipment system 29
20. Prenylation using MAOS 29
21. Structure of montmorillonite 32
22. Clay-catalyzed condensation 33
23. Synthesis of 1,3-dihydroxy-5-methoxyxanthone through method A 38
24. Synthesis of 1,3-dihydroxy-5-methoxyxanthone through method B 39
25. General procedure for the synthesis of P1 and P2 by MW irradiation 39
26. General procedure for the synthesis of P3, P4 and P5 by MW irradiation 40
27. Main connectivities found in HMBC of prenylated xanthones P1-P5 58
28. Examples of HSQC (a) and HMBC (b) spectra of prenylated xanthone P1 58
INDEX OF TABLES

TABLE
1. Mechanisms of action for xanthone derivates with antitumor activity 17
2. Prenylation through MW irradiation and conventional heating 30
3. Main general differences between conventional and MW heating 30
4. Yields obtained with different reaction conditions 33
5. 1H NMR data for compound X1 42
6. 13C NMR data for compound X1 42
7. 1H NMR data for compound X2 43
8. 13C NMR data for compound X2 44
9. 1H NMR data for compound P1 45
10. 13C NMR data for compound P1 46
11. 1H NMR data for compound P2 48
12. 13C NMR data for compound P2 49
13. 1H NMR data for compound P3 50
14. 13C NMR data for compound P3 51
15. 1H NMR data for compound P4 53
16. 13C NMR data for compound P4 54
17. 1H NMR data for compound P5 55
18. 13C NMR data for compound P5 55
19. Effects of the synthesized compounds on the growth of human tumor cell lines 60
ACKNOWLEDGEMENTS

Many were those who contributed towards this work. To those without whom this work
would not have the amount due, I give my special thanks, including:

Faculty of Pharmacy, University of Coimbra.
Faculty of Pharmacy, University of Porto and to CEQUIMED-UP for the facilities to develop the
research work.
Professor Doctor Jorge Salvador, my advisor, for the orientation given in these last two years of
learning; for believing in my capabilities since the beginning and for encouraged me in less easy
moments, helping me to overcome obstacles.
Doctor Raquel Castanheiro, my co advisor, for the experience transmitted and the orientation
given through this work, not only in the laboratory but also outside. For all the readings, questions
and debates that made this thesis possible.
Professor Doctor Madalena Pinto, coordinator of CEQUIMED-UP and director of Laboratory of
Organic and Pharmaceutical Chemistry of Faculty of Pharmacy, University of Porto, for the
opportunity provided to develop my work in this group and for availability on the transmission of
knowledge.
Dr. Sara Cravo, for the expertise, dedication, patience and worry. For fruitful scientific and
personal discussions, always opened to new ideas, which added considerably knowledge not only
to my scientific skills but also to my personal life. For all the help, for the good and untiring
company in long working evenings in the laboratory, for being always present...Thank you!
Professor Doctor Helena Vasconcelos, Doctor Raquel Lima and Diana Sousa from IPATIMUP,
responsible for the biological assays. For the collaboration, the scientific orientation and all the
help and availability.
Professor Doctor Artur Silva from University of Aveiro for the scientific collaboration and
obtaining of NMR spectra.
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