Ionone Is More Than a Violet's Fragrance
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molecules Review Ionone Is More than a Violet’s Fragrance: A Review Lujain Aloum 1 , Eman Alefishat 1,2 , Abdu Adem 1 and Georg Petroianu 1,* 1 Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, UAE; [email protected] (L.A.); Eman.alefi[email protected] (E.A.); [email protected] (A.A.) 2 Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi 127788, UAE * Correspondence: [email protected]; Tel.: +971-50-413-4525 Academic Editor: Domenico Montesano Received: 25 November 2020; Accepted: 8 December 2020; Published: 10 December 2020 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: ionone; biological activity; BCO2; ionone derivatives; cancer; inflammation; OR51E2 1. Chemical Structure, Physicochemical Properties and Natural Occurrence Ionone is a ketone compound composed of 13 carbons with a monocyclic terpenoid backbone [1]. The term ionone derived from “iona” (Greek for violet) referring to the violet scent and “ketone” in relation to its structure [2]. Several isomeric ionones exist in Nature, including α-ionone, β-ionone and others. Ionones are found as secondary plant metabolism products that share mevalonic acid as a common precursor [3]. They are widely present in fruits and vegetables comprising β-carotene and are found in plant oils, for example oils from Petunia hybrida, Boronia megastigma Nees and especially Viola odorata [4–7]. It can be found in cow’s milk where is passively transferred after consumption of alfalfa pasture [8,9]. α-Ionone and β-ionone are 3-buten-2-ones substituted by 2,6,6-trimethyl-2-cyclohexen-1-yl and 2,6,6-trimethyl-1-cyclohexen-1-yl groups respectively, at position 4 (Table1)[ 10,11]. The ionone stereoisomers, α-ionone and β-ionone, are pale yellow-to-yellow liquids [12] with a woody floral scent. However, the former has an extra honey olfactory aspect [13]. α-Ionone and β-ionone share similar physicochemical properties [10–12,14–18]. They are both soluble in most fixed oils, alcohol and propylene glycol but insoluble/very slightly soluble in glycerin/water, respectively [12]. Molecules 2020, 25, 5822; doi:10.3390/molecules25245822 www.mdpi.com/journal/molecules Molecules 2020, 25, 5822 2 of 25 MoleculesMolecules 2020, 202025, x, FOR25, x PEERFOR PEER REVIEW REVIEW 2 of 262 of 26 Molecules 2020, 25, x FOR PEER REVIEW 2 of 26 Table 1. TheTable chemicalTable 1. The 1. chemicalThe structure chemical structure of structureα-ionone of α-ionone of and α-iononeβ and-ionone. βand-ionone. β-ionone. Table 1. Theα chemical-Iononeα-Ionone structure of α-iononeβ -Iononeandβ -Iononeβ-ionone. ReferenceReference α-Ionone β-Ionone Reference α-Ionone O O β-Ionone O O Reference ChemicalChemical O Chemicalstructure structure depiction O [10,11[10,11]] [10,11] Chemical depictiondepiction structure [10,11] depiction α-Ionone andα-Iononeβα-ionone-Ionone and are andβ-ionone both β-ionone widely are areboth used both widely as aromawidely used ingredientsused as aromaas aroma iningredients various ingredients industries, in variousin variousincluding industries, industries, includingincluding cosmetics cosmetics (e.g., (e.g., shampoos, shampoos, soaps) soaps) and andnon-cosmetic non-cosmetic (e.g., (e.g., household household detergents detergents and and cosmetics (e.g., shampoos, soaps) and non-cosmetic (e.g., household detergents and cleaners) products. α-Iononecleaners)cleaners) and products. β-ionone products. The are TheFlavor both Flavor andwidely andExtract Extractused Manufa as Manufa aromacturer’scturer’s ingredients Association Association in(FEMA) various (FEMA) declares industries, declares that thatboth both The Flavor and Extract Manufacturer’s Association (FEMA) declares that both ionones are Generally includingionones cosmeticsionones are Generallyare(e.g., Generally shampoos, Recognized Recognized soaps) As Safe Asand Safe(GRAS) non-cosmetic (GRAS) when when used (e.g., used as flavoring householdas flavoring agents. detergentsagents. The TheUS FDA andUS FDA has has Recognized As Safe (GRAS) when used as flavoring agents. The US FDA has also approved their use cleaners) alsoproducts. alsoapproved approved The their Flavor their use andasuse flavoring asExtract flavoring agentsManufa agents [10,11].cturer’s [10,11]. Association (FEMA) declares that both asionones flavoring are agents Generally [10,11 Recognized]. As Safe (GRAS) when used as flavoring agents. The US FDA has also approved2. Synthesis2. their Synthesis use as flavoring agents [10,11]. 2. Synthesis 2.1. Chemical2.1. Chemical Synthesis Synthesis 2.1.2. ChemicalSynthesis Synthesis VioletViolet scent scent (ionone) (ionone) is currently is currently used used in many in many commercial commercial products products as its as price its price is low. is low. However, However, 2.1.Violet Chemical scentbefore Synthesisbefore (ionone)the 1890s the 1890s isviolet currently violet flower flower usedoil was oil in wasconsidered many considered commercial the mo thest mo precious productsst precious of asall of itsessential all price essential isoils. low. oils.This However, This is because is because the productionthe production of one of onekilogram kilogram of violet of violet oil requoil requires ires33,000 33,000 kg ofkg violet of violet flowers flowers [19], [19], which which cost cost before theViolet 1890s scent violet (ionone) flower is currently oil was considered used in many the commercial most precious products of all as essential its price oils. is low. This However, is because approximatelyapproximately 82,500 82,500 German German gold gold marks marks for raw for rawmaterials. materials. This This costly costly procedure procedure motivated motivated many many thebefore production the 1890s of violet one kilogramflower oil was of violet considered oil requires the most 33,000 precious kg of of all violet essential flowers oils. 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They They Thus in 1893, Tiemann and Krueger investigated the compound responsible for the scent of violets chemists achievedand achievedindustries the synthesisthe to synthesis find ofa cost-efficient ionone of ionone in two in way twosteps. tosteps. synthesizeFirs t,Firs theyt, they performed this performed oil [20]. an aldol an aldol condensation condensation of citral of citral by studyingThuswith orrisin with1893, acetone root acetone Tiemann oil; (dimethyl a (dimethyl much and ketone) cheaper Krueger ketone) in oilan ininvestigat alkaline with an alkaline a similarmeeddium methedium odour compoundto produce to principle produce pseudoionone. responsible pseudoionone. [20,21]. Theyfor Then the Then achieved pseudoionone scent pseudoionone of the synthesisviolets by ofwas iononestudying wascyclized cyclized in orris twoto ionone to steps.root ionone oil;upon First, aupon exposuremuch they exposure cheaper performed to acidic to oilacidic co with annditions co aldol nditionsa similar (Scheme condensation (Scheme odour 1). The 1).principle Thetype of citral type and [20,21]. andconcentration with concentration acetoneThey of of (dimethylachieved ketone) acidthe acidsynthesisused in used andetermines alkaline determinesof ionone the medium in ratiothe two ratio of tosteps.