Alzheimer's disease is an irreversible, degenerative and age-related disease which is growing more and more with the increase in life expectancy. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide. In the present work¸ twenty-seven kaurane diterpenes of natural origin and some readily available derivatives were assayed for acetylcholinesterase inhibition and the structure-activity relationship was analyzed. The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition. In addition, presence of free hydroxyl groups at C-17 and C-19, furnished a diol especially active, able to completely inhibit AChE.

Neste trabalho relatamos uma síntese versátil de quatorze γ-lactonas análogas, dentre as quais nove são inéditas, a partir do furfural prontamente disponível. A atividade fitotóxica dos compostos sintetizados foi avaliada in vitro pela influência no crescimento de coleóptilos de trigo. A maior parte das porcentagens de inibição foi pequena e não diferenciou do controle após a terceira diluição (100 µmol L-1). Em geral, as lactonas α,β-insaturadas apresentaram melhor atividade que as saturadas. Os compostos mais ativos a 1000 µmol L-1 apresentaram inibições de 51, 68 e 76%. Os resultados indicam que, independentemente da saturação, a presença do anel γ-lactonônico é importante para a bioatividade, mas a sua presença não implica necessariamente boa potência.

In this work we report a versatile synthesis of fourteen γ-lactones all structurally related, nine of which are novel compounds, accomplished from the readily available furfural. The phytotoxic activity of the synthesized compounds was evaluated in vitro by the influence on the growth of wheat coleoptiles. The percentages of inhibition were mostly small and not statistically different from control after the third dilution (100 µmol L-1). In general, α,β-unsaturated lactones presented better activities than the saturated ones. The most active compounds presented 51, 68 and 76% of inhibition in 1000 µmol L-1. The results indicate that regardless of saturation, the presence of the γ-lactone moiety is important for the bioactivity, but their presence has no implications with potency.

Hydroxylations of the α-position of lactonic carbonyl groups of four different skeletal types (germacranolides, eudesmanolides, guaianolides, and elemanolides) of 11,13-dihydrosesquiterpene lactones were achieved by LDA-mediated generation of the corresponding lactone enolates and trapping with gaseous oxygen or with a chiral oxidizing agent, (camphorylsulfonyl)oxaziridine. The oxidations with oxygen were non-stereospecific and generated both, the 11 α- and 11β-hydroxylactones in combined yields ranging from 13-47 % along with norsesquiterpene ketones which are most likely formed by decomposition of the hydroperoxide anion intermediates. Hydroxylation of the germacranolide-type 11,13-dihydroparthenolide with either (+)- or (−)-(camphorylsulfonyl)oxaziridine gave exclusively the 11β-hydroxylactone (66-72 %) with no detection of the norsesquiterpene ketone.

Se llevaron a cabo hidroxilaciones de las posiciones α- del grupo carbonilo lactónico en cuatro esqueletos diferentes de 11,13-dihidro- derivados de lactonas sesquiterpénicas (germacranólidas, eudesmanólidas, guayanólidas y elemanólidas), mediante la generación del enolato con LDA y su atrapamiento con oxígeno gaseoso o con un agente oxidante quiral, (canforilsulfonil)aziridina. Las oxidaciones con oxígeno no fueron estereo-específicas y generaron las hidroxilactonas 11α- y 11β- en rendimientos combinados que fluctúan entre 13 al 47 %, junto con cetonas norsesquiterpénicas, que se forman probablemente por la descomposición de los aniones hidroperóxidos intermediarios. La hidroxilación de la germacranólida 11,13-dihidropartenólida, con (+)- o (−)- (canforilsulfonil)-aziridina produjo la 11β-hidroxilactona exclusivamente (66-72 %), sin detectarse la cetona norsesquiterpénica.