RESUMEN
[reaction: see text] A new route toward puupehenone-related bioactive metabolites from (-)-sclareol, based on the palladium(II)-mediated diastereoselective cyclization of a drimenylphenol, is described. Utilizing this, the first enantiospecific synthesis of the antitumor and antimalarial (-)-15-oxopuupehenol, together with improved syntheses of (+)-puupehenone, (+)-puupehedione, and (+)-15-cyanopuupehenone, were accomplished.
Asunto(s)
Antimaláricos/síntesis química , Antineoplásicos/síntesis química , Diterpenos/química , Diterpenos/síntesis química , Sesquiterpenos/química , Xantonas/química , Animales , Antimaláricos/química , Antineoplásicos/química , Estructura Molecular , Poríferos/química , Sesquiterpenos/síntesis química , Estereoisomerismo , Xantonas/síntesis químicaRESUMEN
Chagas disease, caused by the protozoa parasite Trypanosoma cruzi, is an example of extended parasitaemia with unmet medical needs. Current treatments based on old-featured benznidazole (Bz) and nifurtimox are expensive and do not fulfil the criteria of effectiveness, and a lack of toxicity devoid to modern drugs. In this work, a group of abietic acid derivatives that are chemically stable and well characterised were introduced as candidates for the treatment of Chagas disease. In vitro and in vivo assays were performed in order to test the effectiveness of these compounds. Finally, those which showed the best activity underwent additional studies in order to elucidate the possible mechanism of action. In vitro results indicated that some compounds have low toxicity (i.e. >150 µM, against Vero cell) combined with high efficacy (i.e. <20 µM) against some forms of T. cruzi. Further in vivo studies on mice models confirmed the expectations of improvements in infected mice. In vivo tests on the acute phase gave parasitaemia inhibition values higher those of Bz, and a remarkable decrease in the reactivation of parasitaemia was found in the chronic phase after immunosuppression of the mice treated with one of the compounds. The morphological alterations found in treated parasites with our derivatives confirmed extensive damage; energetic metabolism disturbances were also registered by (1)H NMR. The demonstrated in vivo activity and low toxicity, together with the use of affordable starting products and the lack of synthetic complexity, put these abietic acid derivatives in a remarkable position toward the development of an anti-Chagasic agent.
Asunto(s)
Abietanos/química , Abietanos/farmacología , Antiprotozoarios/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Modelos Animales de Enfermedad , Trypanosoma cruzi/efectos de los fármacos , Abietanos/síntesis química , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Enfermedad de Chagas/parasitología , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Células VeroRESUMEN
[structure: see text]. The tetracyclic ketal 24, a suitable intermediate for the synthesis of antitumor pentacyclic quassinoids, has been efficiently prepared from communic acids (5a-c), via methyl ketone 9. The synthetic sequence from 9 to 24 consists of 15 steps in 12% overall yield.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Diterpenos/síntesis química , Cuassinas , Plantas Medicinales/química , TerpenosRESUMEN
A new synthetic strategy toward puupehenone-related bioactive metabolites from sclareol oxide, based on a Diels-Alder cycloaddition approach, is described. Utilizing this, marine ent-chromazonarol and the potent angiogenesis inhibitor 8-epipuupehedione have been synthesized.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Química Orgánica/métodos , Sesquiterpenos/metabolismo , Terpenos/síntesis química , Xantonas/metabolismo , Inhibidores de la Angiogénesis/química , Sesquiterpenos/química , Terpenos/química , Xantenos/síntesis química , Xantonas/químicaRESUMEN
Efficient syntheses of ent-isozonarol (6a), ent-isozonarone (7a) and ent-chromazonarol (8) from (-)-sclareol (12) are described. 6a and 7a show a significative antitumoral activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Xantenos/síntesis química , Xantenos/farmacología , Animales , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Biología Marina , Células Tumorales Cultivadas , Xantenos/químicaRESUMEN
The first syntheses are reported for recently isolated drimanes 11, 12-epoxydrim-8,12-en-11-ol (2) and 11,12-diacetoxydrimane (3), from (-)-sclareol (1). Furthermore, two efficient new routes to the potent bioactive warburganal (4) starting also from 1 are described.