Use of the irritating principal oleocanthal in olive oil, as well as structurally and functionally similar compounds

Abstract

The invention provides methods of synthesizing the purified enantiomers of oleocanthal. The invention further provides methods of using oleocanthals in various formulations including, food additives; pharmaceuticals; cosmetics; animal repellants; and discovery tools for mammalian irritation receptor genes, gene products, alleles, splice variants, alternate transcripts and the like.

1 . A method of synthesizing a purified (−) enantiomer of a compound having the formula: 
     
       
         
         
             
             
         
       
     
     comprising
 (a) converting D-ribose into a compound of Formula I with a strong acid in a suitable solvent; 
 (b) contacting the compound of Formula I with a halogenation reagent followed by metal-halogen exchange induced ring opening to yield a compound of Formula IIa; 
 (c) contacting the compound of Formula IIa with CH 2 ═CH—MgBr in a suitable solvent to yield a compound of Formula IIIa; 
 (d) contacting the compound of Formula IIIa with Grubbs catalyst in a suitable solvent followed by oxidation to yield a compound of Formula IVa; 
 (e) contacting the compound of Formula IVa with hydrogen, palladium catalyst in a suitable solvent to yield (−)-cyclopentanone (Formula Va); 
 (f) contacting the (−)-cyclopentanone with lithium hexamethyldisilazide in a suitable solvent followed by hexamethylphosphoramide (HMPA) dimethyl zinc and alkyl bromoacetate to yield a compound of Formula VIa; 
 (g) subjecting the compound of Formula VIa to a Wittig ethylnation using ethyltriphenylphosphine bromide at reduced temperature; 
 (h) hydrolyzing the ester to yield a compound of Formula VIIIa; 
 (i) contacting the compound of Formula VIIIa with 4-hydroxyphenethyl alcohol under conditions to perform an esterification to yield a compound of Formula IXa; 
 (j) liberating the vicinal diol moiety; and 
 (k) performing an oxidative cleavage to yield (−)-oleocanthal (Formula Xa). 
 
   
   
       2 . A method of synthesizing a purified (+) enantiomer of a compound having the formula: 
     
       
         
         
             
             
         
       
     
     comprising:
 (a) converting D-ribose into a compound of Formula XI with a strong acid in acetone; 
 (b) contacting the compound of Formula XI with a methyltriphenylphosphine bromide, followed by oxidative cleavage to yield a compound of Formula IIb; 
 (c) contacting the compound of Formula IIb with CH 2 ═CH—MgBr in a suitable solvent to yield a compound of Formula IIIb; 
 (d) contacting the compound of Formula IIIb with Grubbs catalyst, in a suitable solvent, followed by oxidation to yield a compound of Formula IVb; 
 (e) contacting the compound of Formula IVb with hydrogen, palladium catalyst in a suitable solvent to yield (+)-cyclopentanone (Formula Vb); 
 (f) contacting the (+)-cyclopentanone with lithium hexamethyldisilazide in a suitable solvent followed by hexamethylphosphoramide (HMPA), dimethyl zinc and methyl bromoacetate to yield a compound of Formula VIb; 
 (g) subjecting the compound of Formula VIb to a Wittig ethylnation using ethyltriphenylphosphine bromide at reduced temperature; 
 (h) hydrolyzing the ester to yield a compound of Formula VIIIb; 
 (i) contacting the compound of Formula VIIIb with 4-hydroxyphenethyl alcohol under conditions to perform an esterification to yield a compound of Formula IXb; 
 (j) liberating the vicinal diol moiety; and 
 (k) performing an oxidative cleavage to yield (+)-oleocanthal (Formula Xb). 
 
   
   
       3 . A compound comprising the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
       wherein said compound is other than oleocanthal. 
     
   
   
       4 . A method of inhibiting COX-1, COX-2, COX-3 or lipoxygenase comprising administering an effective amount of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       5 . The method of  claim 4  wherein said compound is oleocanthal. 
   
   
       6 . The method of  claim 5  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       7 . The method of  claim 5  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       8 . An anti-inflammatory composition comprising a therapeutically effective amount of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     and a pharmaceutically acceptable carrier. 
   
   
       9 . The composition of  claim 8  wherein said compound is oleocanthal. 
   
   
       10 . The composition of  claim 9  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       11 . The method of  claim 9  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       12 . An antioxidant composition comprising a therapeutically effective amount of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     and a pharmaceutically acceptable carrier. 
   
   
       13 . The composition of  claim 12  wherein said compound is oleocanthal. 
   
   
       14 . The composition of  claim 13  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       15 . The method of  claim 13  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       16 . A method of enhancing the flavor of food comprising adding an effective amount of a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       17 . The method of  claim 16  wherein said compound is oleocanthal. 
   
   
       18 . The method of  claim 17  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       19 . The method of  claim 17  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       20 . An animal repellent comprising an effective amount of a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       21 . The animal repellent of  claim 20  wherein said compound is oleocanthal. 
   
   
       22 . The animal repellent of  claim 21  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       23 . The animal repellent of  claim 21  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       24 . The animal repellent of  claim 20  wherein said repellent is in the form of a propellent spray. 
   
   
       25 . A method for treating a sore throat comprising administering to a patient with a sore throat an effective amount of a composition comprising a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     and a pharmaceutically acceptable carrier. 
   
   
       26 . The method of  claim 25  wherein said compound is oleocanthal. 
   
   
       27 . The method of  claim 26  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       28 . The method of  claim 26  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       29 . The method of  claim 25  wherein said composition is in the form of a lozenge. 
   
   
       30 . The method of  claim 25  wherein said composition is in the form of a spray. 
   
   
       31 . A method of preserving food comprising contacting a food with an effective amount of a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       32 . The method of  claim 31  wherein said compound is oleocanthal. 
   
   
       33 . The method of  claim 32  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       34 . The method of  claim 32  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       35 . The method of  claim 31  wherein said compound is incorporated into a film. 
   
   
       36 . The method of  claim 31  wherein said compound is coated onto a packaging material which is in contact with said food. 
   
   
       37 . The method of  claim 31  wherein said compound is added directly to said food. 
   
   
       38 . A method of repelling animals from an edible source comprising adding to an edible source an effective amount of a compound comprising the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       39 . The method of  claim 38  wherein said compound is oleocanthal. 
   
   
       40 . The method of  claim 39  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       41 . The method of  claim 39  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       42 . The method of  claim 38  wherein said compound is added to an edible source otherwise susceptible to consumption by birds. 
   
   
       43 . The method of  claim 38  wherein said compound is added to an edible source otherwise susceptible to consumption by non-human mammals. 
   
   
       44 . The method of  claim 38  wherein said compound is added to an edible source which is toxic to animals upon consumption. 
   
   
       45 . The method of  claim 38  wherein said edible source is antifreeze. 
   
   
       46 . A method of inhibiting sweetness perception in an edible source comprising adding to an edible source a sweetness inhibiting amount of a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       47 . The method of  claim 46  wherein said compound is oleocanthal. 
   
   
       48 . The method of  claim 47  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       49 . The method of  claim 47  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       50 . A method of treating a cold comprising administering to a patient in need of treatment a composition comprising an effective amount of a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       51 . The method of  claim 50  wherein said compound is oleocanthal. 
   
   
       52 . The method of  claim 51  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       53 . The method of  claim 51  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       54 . The method of  claim 50  wherein said compound is administered as a nasal lavage or mist. 
   
   
       55 . A method of treating a patient with an inflammatory disorder comprising administering to a patient with an inflammatory disorder an effective amount of a composition comprising a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     wherein said composition alleviates inflammation in said patient. 
   
   
       56 . The method of  claim 55  wherein said compound is oleocanthal. 
   
   
       57 . The method of  claim 56  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       58 . The method of  claim 56  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       59 . (canceled) 
   
   
       60 . The method of  claim 55  wherein said inflammatory disorder is selected from the group consisting of psoriasis, cancer, asthma, allergic rhinitis, respiratory distress syndrome, inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome, ulcerative colitis, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, ischemic kidney disease, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis, vascular disease myocardial ischemia, heart disease, and stroke. 
   
   
       61 . A method of inhibiting growth of microorganisms comprising contacting microorganisms with an effective amount of a composition comprising a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     wherein said composition inhibits the growth of microorganisms. 
   
   
       62 . The method of  claim 61  wherein said compound is oleocanthal. 
   
   
       63 . The method of  claim 62  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       64 . The method of  claim 62  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       65 . The method of  claim 61  wherein said composition is incorporated into sutures or bandages. 
   
   
       66 . The method of  claim 61  wherein said composition is applied to a wound. 
   
   
       67 . A method for screening for genes associated with oleocanthal sensitivity comprising contacting an expression library formed from an oleocanthal-responsive cell with oleocanthal conjugated to a detectable label; identifying an expression clone that binds said oleocanthal; and sequencing the polynucleotide that encodes the expression clone, thereby identifying a gene associated with oleocanthal sensitivity. 
   
   
       68 . A method of screening for candidate genes associated with oleocanthal sensitivity comprising identifying differentially expressed genes in oleocanthal-responsive cells, obtaining sequences of said differentially expressed genes, comparing sequences of said differentially expressed genes and correlating similarity of said sequences to known that of taste receptors, wherein high homology to a taste receptor thereby identifies a candidate gene associated with oleocanthal sensitivity. 
   
   
       69 . A purified (−) isomer of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       70 . A purified (+) isomer of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       71 . A method of treating pain in a patient comprising administering to a patient an effective amount of a composition comprising a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 ; 
     
     wherein said composition alleviates inflammation in said patient. 
   
   
       72 . The method of  claim 71  wherein said compound is oleocanthal. 
   
   
       73 . The method of  claim 72  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       74 . The method of  claim 72  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       75 . A method of purifying oleocanthal comprising extracting olive oil with 80:20 volume/volume methanol:water to obtain a phenolic extract; pre-fractionating said phenolic extract on a C18 solid phase extraction cartridge; separating oleocanthal by reversed-phase HPLC in a weak gradient and selecting a fraction containing throat irritating activity, thereby purifying oleocanthal. 
   
   
       76 . A method of preventing a neurodegenerative disorder comprising administering to a patient an effective amount of a composition comprising a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 4  are independently H or OR 5    
       R 2  and R 3  are independently CHO, or COOR 5    
       R 5  is a H, C 1 -C 5  alkyl, or a glycoside 
       X is O, NH or CH 2    
       Y is C═CHCH 3 , or CH—COOR 5    
       Z is C═O or CH—OR 5    
       A is CH 2 , or CH—COOR 5 . 
     
   
   
       77 . The method of  claim 76  wherein said compound is oleocanthal. 
   
   
       78 . The method of  claim 77  wherein said oleocanthal is the (−)-enantiomer. 
   
   
       79 . The method of  claim 77  wherein said oleocanthal is the (+)-enantiomer. 
   
   
       80 . The method of  claim 76  wherein said composition prevents production of Aβ42 in said patient. 
   
   
       81 . The method of  claim 76  wherein said neurodegenerative disorder is selected from the group consisting of Alzheimer's disease and cognitive impairment.