ABSTRACT
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.
Subject(s)
Abietanes/chemistry , Abietanes/pharmacology , Antiprotozoal Agents/pharmacology , Chagas Disease/drug therapy , Disease Models, Animal , Trypanosoma cruzi/drug effects , Abietanes/chemical synthesis , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Chagas Disease/parasitology , Chlorocebus aethiops , Dose-Response Relationship, Drug , Female , Mice , Mice, Inbred BALB C , Molecular Conformation , Parasitic Sensitivity Tests , Structure-Activity Relationship , Vero CellsABSTRACT
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.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Chemistry, Organic/methods , Sesquiterpenes/metabolism , Terpenes/chemical synthesis , Xanthones/metabolism , Angiogenesis Inhibitors/chemistry , Sesquiterpenes/chemistry , Terpenes/chemistry , Xanthenes/chemical synthesis , Xanthones/chemistryABSTRACT
[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.
Subject(s)
Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Diterpenes/chemistry , Diterpenes/chemical synthesis , Sesquiterpenes/chemistry , Xanthones/chemistry , Animals , Antimalarials/chemistry , Antineoplastic Agents/chemistry , Molecular Structure , Porifera/chemistry , Sesquiterpenes/chemical synthesis , Stereoisomerism , Xanthones/chemical synthesisABSTRACT
[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.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Diterpenes/chemical synthesis , Quassins , Plants, Medicinal/chemistry , TerpenesABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzofurans/chemical synthesis , Diterpenes/chemistry , Naphthalenes/chemical synthesis , Porifera/chemistry , Sesquiterpenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Drug Screening Assays, Antitumor , Humans , Leukemia P388/drug therapy , Naphthalenes/pharmacology , Sesquiterpenes/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
