Goniotalamina, epoxigoniotalamina, argentilactona e derivados : sinteses totais e atividades antiproliferativas contra celulas tumorais humanas / Goniothalamin, goniothalamin oxide and argentilactone: total syntheses and antiproliferative activies against cells of human cancer

AUTOR(ES)
DATA DE PUBLICAÇÃO

2005

RESUMO

Natural goniothalamin (24), goniothalamin oxide (25) and argentilactone (23) are 5,6-di-hydro-2H-pyran-2-one that display many interesting biological activities. The total syntheses of these natural products as well as some of their derivatives are described. Goniothalamin (24) was synthesized via catalytic asymmetric allylation of a-benzyloxyacetaldehyde (38) by using Keck s protocol, followed by ring-closing metathesis and Wittig [7 steps, 5% overall yield and 94% ee from benzyl alcohol (46)] or Julia-Konciésky olefination [7 steps, 7% overall yield and 94% ee from 46) and via catalytic asymmetric allylation of trans cinnamaldehyde (26) with Maruoka s protocol, followed by ring-closing metathesis [3 steps, 73% overall yield and 95-98% ee from 26]. Goniothalamin oxide (25) and derivatives were synthesized from goniothalamin (24) and argentilactone (23) was obtained using Maruoka s protocol for addition of allyltributyltin to 2-octynal (99) (4 steps, 39% overall yield and 82-84% ee). All compounds evaluated presented antiproliferative activity in a concentration-dependent way. The studies on structure and biological activíty have shown that S absolute configurations as well as the double bond in the pyranyl ring are essential for the antiproliferative activity of the goniotalamin (24) against the cancer cell lines studied, particulary for the kidney carcinome (786-0). Similar results were obtained for (S)-argentilactone [(S)-23]. The presence of electron donating or electron withdrawing groups in the aromatic ring diminishes the potency of (S)-goniothalamin [(S)-24) on the tumor cell growth. Actually, the aromatic ring does not seem to be essential for the potency presented by (S)-24 since its substitution by cyclohexyil group did not affect its activity on the kidney cells (786-0). (S)- e (R)-24 promoted significant morphological changes in kidney cells (786-0) after 6h of treatment. Our studies have demonstrated that at 4 nM and 6.4 mM, the enantiomer of goniotalamin (24) inhibited in 40 and 45%, respectively, lhe Nitric Oxide Synthase (NOS) activity preexistent in kidney cancer cells (786-0). Moreover, ent-isogoniothalamin oxide (ent-90) presented the highest activity among the epoxides evaluated.

ASSUNTO(S)

estiril lactonas alilação assimetrica piranonas cancer pyranones styryl lactones cancer asymmetric allylation

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