Structure activity relationship studies of anti-inflammatory TMMC derivatives: 4-Dimethylamino group on the B ring responsible for lowering the potency

Abstract

We previously synthesized 2',4',6'-tris(methoxymethoxy)chalcone (TMMC) derivatives with various substituents on the A ring that showed potent anti-inflammatory effects by inhibiting NO production in RAW 264.7 cells. The 2'-hydroxy group on the A ring could elevate the electrophilicity of Michael addition of GSH and electron donating groups on the A ring could stabilize the GSH adduct by decreasing the acidity of the alpha-hydrogen. Using this interpretation, we tested various substituents on the B ring and established a proper balance between biological activity and the position of the electron donating or electron withdrawing groups on the B ring. In this case, the 2'-hydroxy group was excluded because it could cause the formation of GSSG through a phenoxy radical and can confuse the interpretation of the biological results. Chalcone derivatives without 2'-hydroxy are likely to deplete cellular GSH levels by a Michael addition process. Strong electron donating groups on the B ring, such as 4-dimethylamino group, gave the weakest inhibition of NO production. A 4-dimethyamino group on the B ring could decrease the stability of the GSH adduct by weakening the C-S bond strength through movement of an electron pair on nitrogen via an aromatic ring.

(E)-2-Benzylidenebenzocyclanones: Part VII. Investigation of the conjugation reaction of two cytotoxic cyclic chalcone analogues with glutathione: an HPLC–MS study

“…At 300 min the absorption of 2 was reduced to 83 %, whereas that of 3 was 70 % of the respective initial values. This observation is in agreement with the expected stability of the adducts which is affected by the different degree of electron donation of the two substituents [8].…”

“…Such a reaction can alter the intracellular redox status (redox signaling), which can modulate events such as DNA synthesis, enzyme activation, selective gene expression, and regulation of the cell cycle [6]. Several biological effects (e.g., NQO1 inducer [7], anti-inflammatory [8], and GST P1-1 inhibitory [9] effects) of chalcones have been associated with their Michael-type reactivity towards reduced glutathione (GSH). It was suggested that the lower GSHdepletion potential of chalcones with strong electron donor substituents (e.g., dimethylamino) on the B ring could be the consequence of the lower Michael-type reactivity of the derivatives towards GSH [8].…”

“…Several biological effects (e.g., NQO1 inducer [7], anti-inflammatory [8], and GST P1-1 inhibitory [9] effects) of chalcones have been associated with their Michael-type reactivity towards reduced glutathione (GSH). It was suggested that the lower GSHdepletion potential of chalcones with strong electron donor substituents (e.g., dimethylamino) on the B ring could be the consequence of the lower Michael-type reactivity of the derivatives towards GSH [8]. On the other hand, higher reactivity towards GSH and other thiols was found to parallel the higher NQO1 inducing potential of the investigated chalcones [7].…”

Reagent‐induced asymmetric induction in addition reaction of reduced glutathione onto bis‐Mannich chalcones

“…Such a reaction can alter intracellular redox status (redox signaling), which can modulate events such as DNA synthesis, enzyme activation, selective gene expression, and regulation of the cell cycle . Several biological effects (e.g., NQO1 inducer, anti‐inflammatory, GST P1‐1 inhibitory) of chalcones have been associated with their Michael‐type reactivity toward reduced glutathione (GSH). It was suggested that the lower GSH depletion potential of chalcones with strong electron donor substituents (e.g., dimethylamino) on the B ring could be the consequence of the lower Michael‐type reactivity of the derivatives toward GSH .…”

Anti-Inflammatory and Anticancer Drugs from Nature

“…Despite their apparent lack of specificity, chalcones were described to target distinct regulatory proteins that modulate downstream signaling pathways. Specific structural requirements play an essential role and can be correlated with observed bioactivity [63][64][65][66][67]. Identification and characterization of natural chalcones as nutraceuticals or as novel therapeutic agents is a promising approach to fight inflammation and cancer [31,32,39].…”