Trends in structure–toxicity relationships for carbonyl-containing α,β-unsaturated compounds

Abstract

Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure-toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between alpha,beta-unsaturated carbonyl compounds with the carbon-carbon double bond on the end of the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of alpha,beta-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation

“…In contrast, the size of the endoperoxide ring (five-membered vs. six-membered) was important, with the six-membered 6-epi-plakortide H acid ( 1 ) being 10-fold more active than the five-membered endoperoxide plakortide E ( 2 ) with the same side chain. Plakortide E ( 2 ) and its methyl ester ( 6 ) also possess a double bond activated by an electron-withdrawing substituent (acid or ester) for nucleophilic attack [50], which might also contribute to cytotoxicity. However, the data did not support this assumption, since the methyl ester of plakortide E ( 6 ) which also contains the activated double bond was inactive.…”

Cell signalling by reactive lipid species: new concepts and molecular mechanisms

“…On the other hand, ‘soft’ electrophiles include many RLS [119] and react readily with ‘soft’ nucleophiles such as GSH and protein cysteinyl thiols [119,121]. In comparison with the cyclopentenone lipid electrophiles, α,β-unsaturated aldehydes including acrolein and isoketals are relatively harder [122], allowing them to adduct to harder nucleophiles including DNA and the amino groups on lysine and lipids. An example of a relatively soft electrophile is 15-PGJ 2 , which reacts with thiol groups on cysteine, but does not modify other nucleophilic amino acids [123–125].…”

“…This is important when considering the ability of RLS to modify proteins thus changing their function and the cellular response. It is now appreciated that site-specific modification of cysteine residues contributes to cell signalling through cysteine rich proteins, such as Keap1, whereas modification of lysine residues is associated with toxicity [21,122,134–137]. …”

Comparison ofTetrahymena pyriformistoxicity based on hydrophobicity, polarity, ionization and reactivity of class-based compounds

“…Most of these industrial organic chemicals exhibit a narcotic mode of toxic action [11,12]. In contrast to the results reported for the most saturated alcohols, primary propargylic alcohols, especially those lower in molecular weight, were shown to exhibit greater toxicity in T. pyriformis than did their saturated analogues.…”