Potency ranking of triterpenoids as inducers of a cytoprotective enzyme and as inhibitors of a cellular inflammatory response via their electron affinity and their electrophilicity index

• Published in: Chemico-biological interactions Vol. 186; no. 2; pp. 118 - 126
• Main Authors: Bensasson, René V., Zoete, Vincent, Berthier, Gaston, Talalay, Paul, Dinkova-Kostova, Albena T.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 30.07.2010
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Binding Sites; Electron affinity; Enzyme Induction - drug effects; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Inflammation; Ligands; Models, Chemical; NAD(P)H Dehydrogenase (Quinone) - biosynthesis; NAD(P)H-quinone oxidoreductase 1; Nitric Oxide Synthase Type II - antagonists & inhibitors; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Quantum chemical calculations; Static Electricity; Structure-Activity Relationship; Structure–activity relationships; Triterpenes - chemistry; Triterpenes - pharmacology; Inflammation; NAD(P)H-quinone oxidoreductase 1; Quantum chemical calculations; Structure–activity relationships; Electron affinity
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2010.04.026

Electron affinity ( EA) and electrophilicity index ( ω) of 16 synthetic triterpenoids (TP), previously identified as inducers of cytoprotective enzymes and as inhibitors of cellular inflammatory responses, have been calculated by the molecular orbital method. Linear correlations were obtained by plotting the values of EA, as well as those of ω versus (i) the potencies of induction of NAD(P)H quinone reductase (NQO1, EC 1.6.99.2), a cytoprotective enzyme, expressed via the concentration of TP required to double the specific activity of NQO1 (CD value) and (ii) the values of their anti-inflammatory activity expressed via the IC-50 of TP for suppression of upregulation of inducible nitric oxide synthase (iNOS, EC 1.14.13.39), both previously experimentally determined. The observed correlations demonstrate quantitatively for a series of triterpenoids that their electrophilicity is a major factor determining their potency as inducers of the cytoprotective phase 2 response and as inhibitors of inflammatory processes.