IJUP08 - Universidade do Porto

Synthesis and Determination of Physicochemical Parameters of
Xanthones
C. Azevedo 1,2 , C. M. M. Afonso 2 , M. M. M. Pinto 2 , J. L. F. C. Lima 1 and S. Reis 1
1 REQUIMTE – Serviço de Química-Física, Faculdade de Farmácia, Universidade do Porto
2 CEQOFFUP – Serviço de Química Orgânica, Faculdade de Farmácia, Universidade do Porto.
Rua Aníbal Cunha 164, 4050-047 Porto, Portugal
Natural and synthetic xanthones have revealed a vast diversity of biological activities and
the xanthone nucleus has shown to be a good platform for the development of new
pharmacological active compounds [1]. To transform a biological active compound in a
successful drug it requires, among several other procedures, the synthesis of new
molecules and the understanding of both pharmacodynamic and pharmacokinetic
behaviours [2]. The objective of this work was to synthesize two series of xanthones and to
evaluate their physicochemical parameters in order to establish models of pharmaceutical
behaviour for xanthone compounds.
It was synthesized, by classic methodologies and with the aid of microwaves, series of
mono-hydroxylated and mono-methoxylated xanthones. The parameters studied were the
partition coefficients and the acidity constants. So, it was possible to study the influence of
two types of substituents in the xanthone nucleous: the hydroxyl (polar) and methoxyl (less
polar) groups.
The partition coefficient of the xanthones was studied in micelles of
hexadecylphosphocoline (HDPC), and determined by derivative spectroscopy [3]. In the
mono-hydroxylated series, the more lipophilic compound was 2-hydroxyxanthone and less
lipophilic compounds were 3-hydroxyxanthone and 4-hydroxyxanthone. In the
monomethoxylated series, the more lipophilic compounds were 2-methoxyxanthone and 3methoxyxanthone
and the less lipophilic compound was 1-methoxyxanthone.
The acidity constants, at 25 ºC and with ionic strength of 0,15 mol dm -3 (NaCl), of monohydroxylated
xanthones were determined by spetrophotometric titration, using the
Hyperquad 2006 software [4]. The results have shown that the more acidic xanthones were
3-hydroxyxanthone and 4-hydroxyxanthone, and the less acidic were 1-hydroxyxanthone
and 2-hydroxyxanthone.
Mechanistic and structure-physicochemical values relationships were rationalized and can
explain the obtained data for the different compounds in this study.
[1] Pinto, M.M.M., Sousa, M.E. and Nascimento, M.S.J. (2005), Xanthone derivatives: New
insights in biological activities, Current Medicinal Chemistry, 12 (21), 2517-2538.
[2] Kerns, E.H. and Di L. (2003), Pharmaceutical Profiling in Drug Discovery, Drug Discovery
Today, 8 (7), 316-323.
[3] Castro, B., Gameiro, P., Lima, J.L.F.C., Matos, C. and Reis, S. (2001), Interaction of drugs with
hexadecylphosphocholine micelles. Derivative spectroscopy, acid-base and solubility studies,
Materials Science and Engineering: C, 18 (1-2), 71-78.
[4] Gans, P., Sabatini, A. and Vacca, A. (1996), Investigation of equilibria in solution.
Determination of equilibrium constants with the HYPERQUAD suite of programs, Talanta, 43
(10), 1739-1753.
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