the recently reported inhibition of focal adhesion kinase 1 by parthenolide, 5a,b the cytotoxic activity of dehydroleucodine against human leukemia cells, 8 or the ability of nimbolide to inhibit metastasis. 4,5 The ability of these biomolecules to react as electrophiles with nucleophilic sites furnishes them with a multitude of biological functions, 6,7 e.g. 1–3 Previous studies of their cellular reactivities with endogenous proteins revealed intriguing insights into their target profiles. Introduction Cyclic carbonyl compounds with α,β-unsaturated positions are important motifs within many natural products ( Chart 1). The electrophilicities of simplified electrophilic fragments reflect the general reactivity pattern of structurally more complex terpene-derived cyclic enones and sesquiterpene lactones, such as parthenolide. The observed reactivity trends were rationalized through quantum-chemically calculated Gibbs energy profiles (at the SMD(DMSO)/M06-2X/6-31+G(d,p) level of theory) and distortion interaction analysis for the reactions of the cyclic Michael acceptors with a sulfonium ylide. While cyclization reduces the reactivity of enones slightly, α,β-unsaturated lactones are significantly more reactive Michael acceptors than analogously substituted open-chain esters. Cyclic enones and lactones show different reactivity trends than their acyclic analogs. The experimentally determined second-order rate constants k 2 were analyzed with the Mayr–Patz equation, lg k = s N( N + E), to furnish the electrophilicity descriptors E for the Michael acceptors. The electrophiles and nucleophiles in the database are classified by stars.The reactivities of cyclic enones and α,β-unsaturated lactones were characterized by following the kinetics of their reactions with colored carbon-centered reference nucleophiles in DMSO at 20 ☌. This is quite helpful in view of the fact that Equation (1) presently covers a reactivity range of 40 orders of magnitude.Īs carbon-centered electrophiles and carbon-centered nucleophiles have been used for the parameterization, Equation (1) is only applicable when one or both reaction centers are carbon.ĭo not use the reactivity parameters for predicting reactions with bulky reagents (for exceptions see entries for tritylium ions) While rate constants k for the reactions with reference electrophiles are usually reproduced with deviations of less than a factor of 2, deviations by a factor of 10 to 100 have to be expected, when both reaction partners are not from the reference sets. S N = nucleophile-specific sensitivity parameter (solvent dependent)īe aware of the fact, that the three-parameter Equation (1) does not include steric effects and, therefore, can only be used for semiquantitative predictions of rate constants. N = nucleophilicity parameter (solvent dependent) ![]() ![]() ![]() The database contains a compilation of the published reactivity parameters E, N, and s N which allow to calculate the rate constants for combination reactions of electrophiles with nucleophiles by Equation (1) : S-Electrophiles (thiolating reagents) (9). ![]()
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