Ionone Is More than a Violet's Fragrance: A Review

Abstract

The term ionone is derived from "iona" (Greek for violet) which refers to the violet scent and "ketone" due to its structure. Ionones can either be chemically synthesized or endogenously produced via asymmetric cleavage of β-carotene by β-carotene oxygenase 2 (BCO2). We recently proposed a possible metabolic pathway for the conversion of α-and β-pinene into α-and β-ionone. The differences between BCO1 and BCO2 suggest a unique physiological role of BCO2; implying that β-ionone (one of BCO2 products) is involved in a prospective biological function. This review focuses on the effects of ionones and the postulated mechanisms or signaling cascades involved mediating these effects. β-Ionone, whether of an endogenous or exogenous origin possesses a range of pharmacological effects including anticancer, chemopreventive, cancer promoting, melanogenesis, anti-inflammatory and antimicrobial actions. β-Ionone mediates these effects via activation of olfactory receptor (OR51E2) and regulation of the activity or expression of cell cycle regulatory proteins, pro-apoptotic and anti-apoptotic proteins, HMG-CoA reductase and pro-inflammatory mediators. α-Ionone and β-ionone derivatives exhibit anti-inflammatory, antimicrobial and anticancer effects, however the corresponding structure activity relationships are still inconclusive. Overall, data demonstrates that ionone is a promising scaffold for cancer, inflammation and infectious disease research and thus is more than simply a violet's fragrance.

Keywords: BCO2; OR51E2; biological activity; cancer; inflammation; ionone; ionone derivatives.

Scheme 1

The chemical synthesis of ionones via the Tiemann-Krueger synthesis. Citral and acetone are condensed in an alkaline medium to yield pseudoionone. Pseudoionone is cyclized to ionone upon exposure to acidic conditions. Phosphoric, fumaric and other weaker acids mainly yield α-ionone, while concentrated sulfuric acid preferentially yields β-ionone.

Scheme 2

The enzymatic cleavage of β-carotene by β-carotene oxygenase 1 (BCO1) and β-carotene oxygenase 2 (BCO2). The central cleavage of β-carotene catalyzed by BCO1 at the 15,15′ double bond results in the formation of two molecules of all-trans retinal. The asymmetric cleavage of β-carotene at the 9,10 double bond facilitated by BCO2 results in generation of β-ionone and β-10′-apocarotenal. Another cleavage at the 9′,10′ double bond yields an additional β-ionone moiety and rosafluene.

Scheme 3

Possible metabolic conversion of α- and β-pinene to α- and β-ionone (modified from [43]).

Figure 1

A proposed scheme illustrating the effect of β-ionone mediated activation of membrane and cytosolic OR51E2 receptor leading to an increase in calcium and regulation of various kinases modulating cell proliferation, metastasis and melanogenesis. (OR51E2, olfactory receptor 51E2; BCO2, β-carotene oxygenase 2; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; TRP calcium channel, transient receptor potential calcium channel; Pyk2, proline-rich tyrosine kinase 2; MAPK, mitogen-activated protein kinase; SAPK/JNK, stress-activated protein kinases/Jun amino-terminal kinases; NDRG1, N-myc downstream regulated gene 1; AR, androgen receptor; AKT, protein kinase B; PI3Kɣ, phosphoinositide 3-kinase gamma).

Figure 2

β-Ionone modulates several cell cycle regulatory proteins causing cell cycle arrest in various cancer cells (Cdk-1, cyclin-dependent kinase-1; Cdk-2, cyclin-dependent kinase-2; Cdk-4, cyclin-dependent kinase-4; p27, cyclin-dependent kinase inhibitor; p21, cyclin-dependent kinase inhibitor).

Figure 3

A proposed mechanism of β-ionone modulating pro-apoptotic and anti-apoptotic pathways. (OR51E2, olfactory receptor 51E2; BCO2, β-carotene oxygenase 2; JNK, Jun amino-terminal kinases; AKT, protein kinase B; PI3K, phosphoinositide 3-kinase; Apaf-1, apoptotic protease activating factor 1; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; DR4/5, death receptor 4/5; NF-кB, nuclear factor-κB; transcription factor SP1; specificity protein 1; DR5 promoter, death receptor 5 promoter).

Figure 4

β-Ionone-mediated inhibition of HMG-CoA reductase resulting in anti-proliferative effect and reduction in the level of cholesterol. (OR51E2, olfactory receptor 51E2; BCO2, β-carotene oxygenase-2; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; PP, pyrophosphate).

Figure 5

β-Ionone inhibition of pro-inflammatory mediators and induction/restoration of antioxidants causing anti-proliferative and anti-inflammatory effects. (OR51E2, olfactory receptor 51E2; BCO2, β-carotene oxygenase-2; MAPK, mitogen-activated protein kinase; JNK, Jun amino-terminal kinases; AKT, protein kinase B; NF-кB, nuclear factor-κB; Erk1/2, extracellular signal-regulated kinase 1/2; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GST, glutathione-S-transferase; GR, glutathione reductase; GSH, glutathione).

Figure 6

3-Hydroxy-β-ionone. The β-ionone moiety is shown in red.

Figure 7

5,6-Epoxy-β-ionone. The β-ionone moiety is shown in red.

Figure 8

(Compound a). R = H, R’ = H, R’’ = NO₂; [(1E,4E)-1-(4-nitrophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl) penta-1,4-dien-3-one]; (compound b). R = H, R’ = CF₃, R’’ = H; [(1E,4E)-1-(3-(trifluoromethyl)phenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one] (compound c). R = NO₂, R’ = H, R” = H [(1E,4E)-1-(2-nitrophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one]; (compound d). R = Cl, R’ = H, R” = H [(1E,4E)-1-(2-chlorophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one]; (compound e). R = Br, R’ = H, R” = H; [(1E,4E)-1-(2-bromophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one]. The β-ionone moiety is shown in red.

Figure 9

(1E,4E)-1-(Benzo[b]thiophen-3-yl)-5-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien -3-one. The β-ionone moiety is shown in red.

Figure 10

(Compound a). R = H; [(1E,6E)-4-((Z)-4-hydroxy-3-methoxybenzylidene)-1-(4-hydroxy-3-methoxy phenyl)-7-(2,6,6-trimethylcyclohex-1-en-1-yl)hepta-1,6-diene-3,5-dione] (compound b). R = OH; [(1E,6E)-1-(3- hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-4-((Z)-4-hydroxy-3-methoxybenzylidene)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione]. The β-ionone moiety is shown in red.

Figure 11

(Compound a). R = H; [(E)-5-(2-(2,6,6-trimethylcyclohex-2-en-1-yl)vinyl)-1H-pyrazole] (compound b). R = 4-amino-4H-1,2,4-triazole-3-thiol; [(E)-4-amino-5-(5-(2-(2,6,6-trimethylcyclohex-2-en-1-yl)vinyl)-1H-pyrazol-1 -yl)-4H-1,2,4-triazole-3-thiol] (compound c). R = phenyl [(E)-1-phenyl-5-(2-(2,6,6-trimethylcyclohex-2-en-1-yl)vinyl)-1H-pyrazole]. The α-ionone moiety is shown in blue.

Figure 12

(E)-2-(Methylthio)-4-(2-(2,6,6-trimethylcyclohex-2-en-1-yl)vinyl)pyrimidine. The α-ionone moiety is shown in blue.

Figure 13

(Compound a). R = Cl; [10-(11-chloroethyl)-7-(1,1,5-trimethylcyclohex-5-en-6-yl)dihydrofuran-2(3H)-one]; (compound b). R = OH [10-(11-hydroxyethyl)-7-(1,1,5-trimethylcyclohex-5-en-6-yl)dihydrofuran-2(3H)-one]; (compound c). R = Br [10-(11-bromoethyl)-7-(1,1,5-trimethylcyclohex-5-en-6-yl)dihydrofuran-2(3H)-one]. The β-ionone moiety is shown in red.

Figure 14

(E)-4-(methylthio)-6-(2-(2,6,6-trimethylcyclohex-1-en-1-yl)vinyl)pyrimidin-2-amine. The β-ionone moiety is shown in red.