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

Abstract

Xanthones or xanthen-9-ones (dibenzo-g-pirone) comprise an important class of oxygenated heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents. To obtain more structural diversity and quantities for biological assays, suitable and efficient synthetic processes are necessary. Different synthetic methodologies, “classical” and “non-classical”, namely microwave assisted organic synthesis, heterogeneous catalysis and a combination of heterogeneous catalysis with microwave irradiation, were applied to obtain new xanthone derivatives. Thus, this thesis reports the synthesis and structure elucidation of seven new compounds: 1,3-dihydroxy-5-methoxyxanthone (X1), 1-hydroxy-3-mesyloxy-5-methoxyxanthone (X2), 1-hydroxy-5-methoxy-3-(3-methylbut-2-enyloxy)xanthone (P1), 1-hydroxy-5-methoxy-4-(3-methylbut-2-enyl)-3-(3-methylbut-2-enyloxy)xanthone (P2), 1-hydroxy-5-methoxy-4-(3-methylbut-2-enyl)-6’,6’-dimethyl-’,5’-dihydropyran(2’,3’:3,2) xanthone (P3), 1-hydroxy-5-methoxy-6’,6’-dimethyl-’,5’-dihydropyran(2’,3’:3,2)xanthone (P4) and 1-hydroxy-5-methoxy- 6’,6’-dimethyl-’,5’-dihydropyran(2’,3’:3,4)xanthone (P5), as well as the evaluation of their antitumor activity. The synthesized xanthones and respective derivatives with prenyl units were structurally elucidated by spectroscopic methods including IR, NMR (1H, 13C, HSQC and HMBC) and HRMS. Their biological activity was evaluated by a screening assay for inhibition of growth of human tumor cell lines.

As xantonas ou xanten-9-onas (dibenzo-g-pirona) constituem uma importante classe de heterociclos oxigenados com um papel bem conhecido na Química Medicinal. As atividades biológicas desta classe de compostos estão relacionadas com o seu esqueleto tricíclico e variam consoante a natureza e/ou posição dos diferentes substituintes. De forma a obter maior diversidade estrutural e quantidades para ensaios biológicos, são necessários processos sintéticos adequados e eficientes. Diferentes metodologias sintéticas, “clássicas” e “não-clássicas”, nomeadamente síntese orgânica assistida por micro-ondas, catálise heterogénea e a combinação de catálise heterogénea com radiação micro-ondas, foram aplicadas para obter novos derivados xantónicos. Assim, esta tese descreve a síntese e elucidação estrutural de sete novos compostos: 1,3- di-hidroxi-5-metoxixantona (X1), 1-hidroxi-3-mesiloxi-5-metoxixantona (X2), 1-hidroxi-5-metoxi-3- (3-metilbut-2-eniloxi)xantona (P1), 1-hidroxi-5-metoxi-4-(3-metilbut-2-enil)-3-(3-metilbut-2- eniloxi)xantona (P2), 1-hidroxi-5-metoxi-4-(3-metilbut-2-enil)-6’,6’-dimetil-4’,5’di-hidropirano(2’,3’:3,2) xantona (P3), 1-hidroxi-5metoxi-6’,6’-dimetil-4’,5’-di-hidropirano(2’,3’:3,2)xantona (P4) e 1-hidroxi-5- metoxi-6’,6’-dimetil-4’,5’-di-hidropirano(2’,3’:3,4)xantona (P5), assim como a avaliação da sua atividade antitumoral. As xantonas e os respetivos derivados prenilados sintetizados foram caraterizados estruturalmente por métodos espetroscópicos, nomeadamente IV, RMN (1H, 13C, HSQC e HMBC) e EM de alta resolução. A sua atividade biológica foi avaliada através de um screening para a inibição de crescimento de linhas celulares tumorais humanas.