Structure−Cytotoxicity Relationships of Some Helenanolide-Type Sesquiterpene Lactones

Abstract

This study deals with the cytotoxicity of helenanolide-type (10 alpha-methylpseudoguaianolide) sesquiterpene lactones. We determined the influence of substitution patterns on the toxicity of 21 helenanolides to a cloned Ehrlich ascites tumor cell line, EN2. Within a series of helenalin esters, the acetate (2) and isobutyrate (3) were more toxic than helenalin itself (1). Esters with larger acyl groups (tiglate 4 and isovalerate 5) exhibited a decreased toxicity compared with the parent alcohol (1). Similar relationships were observed between the 6,8-diastereomer of helenalin, mexicanin I (6) and its acetate (7) and isovalerate (8). In contrast, cytotoxicity within a series of 11 alpha, 13-dihydrohelenalin esters (9-12) was shown to be directly related to the size and lipophilicity of the ester side chain, dihydrohelenalin (9) being the least toxic compound in this group. Investigation of several 2,3-dihydrohelenalin derivatives (13-21) with 2 alpha-hydroxy-4-oxo- and 2 alpha,4 alpha-dihydroxy- or -O-acyl-substituted cyclopentane rings (arnifolins and chamissonolides, respectively), for which no pharmacological data have been reported so far, revealed further interesting influences of the substitution pattern on cytotoxicity. The results may be interpreted in terms of lipophilicity and steric effects on the accessibility of the reactive sites considered responsible for biological activity.

In Vitro Antitumor Activity of Sesquiterpene Lactones from Lychnophora trichocarpha

“…Alkylation of α,β-unsaturated carbonyl molecules by biological nucleophiles, in a Michaeltype addition, is considered to be the general mechanism of action (Beekman et al, 1997) of compounds presenting this moiety. In the case of eremantholides, the eletrophilic center, that would be responsible for its antitumor activity, is the carbon five (Mc Dougal et al, 1989).…”

“…Covalent binding of sesquiterpene lactones to free sulfydryl groups in proteins may interfere with the functions of these macromolecules. Consequently, sesquiterpene lactones would inhibit a large number of enzymes involved in key biological processes, namely DNA and RNA synthesis, protein and purine syntheses, glycolysis, citric acid cycle, and the mitochondrial PC3 electron transport chain (Beekman et al, 1997).…”

“…The solvent was removed under reduced pressure to afford the ethanol extract (900.0 g). The extract (900.0 g) was submitted to column chromatography on silica gel eluting with n-hexane, n-hexane:ethyl acetate (Le Quesne et al 1978;Bohlmann et al, 1980;Vichnewiski et al, 1989;Saúde et al, 1998;Saúde-Guimarães et al, 2007).…”

“…Sesquiterpene lactones are natural products occurring in many plant families, but most widely distributed within the Asteraceae (Bohlmann et al, 1980). These substances are known to present a variety of biological effects including antitumor activity (Rodrigues et al, 1976).…”

Atividade antibacteriana de furanoeliangólidos

“…Estudos realizados para verificar a relação estrutura-atividade citotóxica de lactonas sesquiterpênicas revelaram que a presença da porção α-metileno-γ-lactona é essencial para a atividade, e que a presença de grupos, como ésteres insaturados, ciclopentenona ou α-metileno-γ-lactona aumenta a citotoxicidade. O mecanismo geral das atividades citotóxica e antitumoral ocorre através de reações do sistema α-metileno-γ-lactona e de outros sistemas conjugados, com grupos sulfidrila das enzimas que controlam a divisão celular, inibindo assim a síntese de proteínas e do DNA (KUPCHAN et al, 1971, BEEKMAN et al, 1990. A atividade antibacteriana dos compostos 1 e 7, ativos contra um número maior de microrganismos, poderia estar relacionada com a porção α-metileno-γ-lactona, uma vez que os compostos 4 e 5, que foram ativos apenas contra um dos microrganismos testados e os compostos inativos 2, 3 e 6 não possuem este grupo.…”