Water Soluble and Activable Phenolics Derivatives with Dermocosmetic and Therapeutic Applications and Process for Preparing Said Derivatives

Abstract

The invention relates to the preparation of phenolics derivatives by enzymatic condensation of phenolics selected among pyrocatechol or its derivatives with the glucose moiety of sucrose. The production of said phenolics derivatives is achieved with a glucosyltransferase (EC 2.4.1.5). These O-α-glucosides of selected phenolics are new, have a solubility in water higher than that of their parent polyphenol and have useful applications in cosmetic and pharmaceutical compositions, such as antioxidative, antiviral, antibacterial, immune-stimulating, antiallergic, antihypertensive, antiischemic, antiarrhythmic, antithrombotic, hypocholesterolemic, antilipoperoxidant, hepatoprotective, anti-inflammatory, anticarcinogenic antimutagenic, antineoplastic, anti-thrombotic, and vasodilatory formulations, or in any other field of application.

1 - 25 . (canceled) 
   
   
       26 . A method for producing a phenolic compound O-α-glucoside comprising incubating sucrose and a glucansucrase from  Leuconostoc  species with a phenolic compound having the following formula: 
     
       
         
         
             
             
         
       
       wherein 
       R2 is H or OH; and 
       R1 is selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       wherein R3 and R4, independently, are H or OH, with the proviso that at least one among R3 and R4 represents OH; 
     
     
       
         
         
             
             
         
       
       wherein R7 is selected from the group consisting of H, —OH or —OCOR and R8 is H or OH, with the proviso that at least one among R7 and R8 represents OH; 
     
     
       
         
         
             
             
         
       
       wherein R5 is OH or OCH 3 ; R6 is H or OH, R9 is H or OH, R10 is H, OCH 3  or C 6 H 11 O 5 , and R11 is H, OH or C 6 H 11 O 5 , with the proviso that R10 and R11 can not be both H when R5 and R6 are both OH and that when R10 is C 6 H 11 O 5  then R11 is H; 
       —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR, with n being an integer from 0 to 2; 
       —(CR12=CH)—COOR or —(CR12=CH)—CONHR, R12 being H or a C 1 -C 6  linear or cyclic alkyl or alkenyl; 
       —(CH 2 ) n —OR or —(CH 2 ) n —NHR with n being an integer from 0 to 2; 
       —(CH 2 ) n —COR or —(CH═CH) n —COR with n being an integer from 0 to 2; 
       —H; 
     
     
       
         
         
             
             
         
       
       a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a bicyclic or tricyclic fused ring together with the ortho carbon of R1, wherein said ring can be interrupted by at least one heteroatom; 
       wherein R is H or a linear, branched, or cyclic, aromatic or non-aromatic, saturated or unsaturated, C 1 -C 10  hydrocarbon group, that may be interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkenyl, or an alkynyl, which can be substituted by one or several substituents selected from the group consisting of an (C 5 -C 9 )aryl, an (C 4 -C 9 )heterocycle, an (C 1 -C 3 )alkoxy, an (C 2 -C 3 )acyl, an (C 1 -C 3 )alcohol, a carboxylic group (—COOH), an (C 2 -C 3 )ester, an (C 1 -C 3 )amine, an amino group (—NH 2 ), an amide (—CONH 2 ), an (C 1 -C 3 )imine, a nitrile, an hydroxyl (—OH), an aldehyde group (—CHO), an halogen, an (C 1 -C 3 )halogenoalkyl, a thiol (—SH), a (C 1 -C 3 )thioalkyl, a (C 1 -C 3 )sulfone, a (C 1 -C 3 )sulfoxide, and a combination thereof. 
     
   
   
       27 . The method according to  claim 26 , wherein R1 of the phenolic compound is 
     
       
         
         
             
             
         
       
       wherein R3 and R4, independently, are H or OH, with the proviso that at least one among R3 and R4 represents OH. 
     
   
   
       28 . The method according to  claim 27  wherein said phenolic compound is taxifolin, eriodictyol, dihydrorrobinetin or fustin. 
   
   
       29 . The method according to  claim 26 , wherein R1 of the phenolic compound is 
     
       
         
         
             
             
         
       
       wherein R7 is selected from the group consisting of H, —OH or —OCOR and R8 is H or OH, with the proviso that at least one among R7 and R8 represents OH. 
     
   
   
       30 . The method according to  claim 29 , wherein said phenolic compound is selected from catechin, epicatechin, catechin gallate, epicatechin gallate, gallocatechin, epigallocatechin, gallocatechin gallate and epigallocatechin gallate. 
   
   
       31 . The method according to  claim 26 , wherein R1 of the phenolic compound is 
     
       
         
         
             
             
         
       
       wherein R5 is OH or OCH 3 ; R6 is H or OH, R9 is H or OH, R10 is H, OCH 3  or C 6 H 11 O 5 , and R11 is H, OH or C 6 H 11 O 5 , with the proviso that R10 and R11 can not be both H when R5 and R6 are both OH and that when R10 is C 6 H 11 O 5  then R11 is H. 
     
   
   
       32 . The method according to  claim 31 , wherein the phenotic compound is selected from the group consisting of rhamnetin, fisetin, robinetin, gossypetin, orientin, homoorientin and cirsiliol. 
   
   
       33 . The method according to  claim 26 , wherein R1 of the phenolic compound is —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR with n being an integer from 0 to 2. 
   
   
       34 . The method according to  claim 33 , wherein the phenolic compound is selected from the group consisting of homoprotocatechuic acid, dihydrocaffeic acid, protocatechuic acid ethyl ester, propyl gallate, gallic acid, hamamelitannin (2′,5-di-O-galloyl-hamamelose) and protocatechuic acid. 
   
   
       35 . The method according to  claim 26 , wherein R1 of the phenolic compound is —(CR12=CH)—COOR or —(CR12=CH)—CONHR, R12 being H or a C 1 -C 6  linear, branched or cyclic alkyl or alkenyl. 
   
   
       36 . The method according to  claim 35 , wherein the phenolic compound is selected from the group consisting of caffeic acid, rosmarinic acid, esculetin, 4-methylesculetin, nordalbergin, chlorogenic acid, caffeic acid phenethyl ester, chicoric acid, echinacoside and verbascoside. 
   
   
       37 . The method according to  claim 26 , wherein R1 of the phenolic compound is —(CH 2 ) n —COR or —(CH═CH) n —COR with n being an integer from 0 to 2. 
   
   
       38 . The method according to  claim 37 , wherein the phenolic compound is selected from the group consisting of maclurine 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzophenone, butein, 3,4-dihydroxyacetophenone, marein, and eriodictyolchalcone. 
   
   
       39 . The method according to  claim 26 , wherein R1 of the phenolic compound is selected from the group consisting of:
 a) —(CH 2 ) n —OR or —(CH 2 ) n —NHR with n being an integer from 0 to 2;   b) —H;   
     
       
         
         
             
             
         
       
     
   
   
       40 . The method according to  claim 26 , wherein R1 of the phenolic compound is a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a bicyclic or tricyclic fused ring together with the ortho carbon of R1, wherein said ring may be interrupted by at least one heteroatom. 
   
   
       41 . The method according to  claim 39 , wherein the phenolic compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       42 . A phenolic compounds O-α-glucoside having the following formula: 
     
       
         
         
             
             
         
       
       wherein: 
       A and B, identical or different, are H or a α-glucosyl residue, with the proviso that at least one of A and B is a α-glucosyl residue; 
       R2 is H or OH; and 
       R1 is selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       wherein R3 and R4, independently, are H or OH, with the proviso that at least one among R3 and R4 represents OH; 
     
     
       
         
         
             
             
         
       
       wherein R7 is selected from the group consisting of H, —OH or —OCOR and R8 is H or OH, with the proviso that, when R2 is H, R7 and R8 are not both OH, and at least one among R7 and R8 is OH; 
     
     
       
         
         
             
             
         
       
       wherein R5 is OH or OCH 3 ; R6 is H or OH, R9 is H or OH, R10 is H, OCH 3  or C 6 H 11 O 5 , and R11 is H, OH or C 6 H 11 O 5 , with the proviso that R10 and R11 can not be both H when R5 and R6 are both OH and that when R10 is C 6 H 11 O 5  then R11 is H; 
       —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR, with n being an integer from 0 to 2; 
       —(CR12=CH)—COOR or —(CR12=CH)—CONHR, R12 being H or a C 1 -C 6  linear, branched or cyclic alkyl or alkenyl; 
       —(CH 2 ) n —OR or —(CH 2 ) n —NHR with n being an integer from 0 to 2; 
       —(CH 2 ) n —COR or —(CH═CH), —COR with n being an integer from 0 to 2; 
       —H; 
     
     
       
         
         
             
             
         
       
       a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a bicyclic or tricyclic fused ring together with the ortho carbon of R1, and wherein said ring may be interrupted by at least one heteroatom; 
       wherein R is H or a linear, branched, or cyclic, aromatic, non-aromatic, saturated or unsaturated C 1 -C 10  hydrocarbon group, that may be interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkenyl, or an alkynyl, which can be substituted by one or several substituents selected from the group consisting of an (C 5 -C 9 )aryl, an (C 4 -C 9 )heterocycle, an (C 1 -C 3 )alkoxy, an (C 2 -C 3 )acyl, an (C 1 -C 3 )alcohol, a carboxylic group (—COOH), an (C 2 -C 3 )ester, an (C 1 -C 3 )amine, an amino group (—NH 2 ), an amide (—CONH 2 ), an (C 1 -C 3 )imine, a nitrile, an hydroxyl (—OH), an aldehyde group (—CHO), an halogen, an (C 1 -C 3 )halogenoalkyl, a thiol (—SH), a (C 1 -C 3 )thioalkyl, a (C 1 -C 3 )sulfone, a (C 1 -C 3 )sulfoxide, and a combination thereof. 
     
   
   
       43 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is 
     
       
         
         
             
             
         
       
     
   
   
       44 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is 
     
       
         
         
             
             
         
       
     
   
   
       45 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is 
     
       
         
         
             
             
         
       
     
   
   
       46 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR with n being an integer from 0 to 2. 
   
   
       47 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is —(CR12=CH)—COOR or —(CR12=CH)—CONHR, R12 being H or a C 1 -C 6  linear or cyclic alkyl or alkenyl. 
   
   
       48 . The phenolic compound O-α-glucoside according to  claim 40 , wherein R1 is —(CH 2 ) n —OR or —(CH 2 ) n —NHR with n being an integer from 0 to 2. 
   
   
       49 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is —(CH 2 ) n —COR or —(CH═CH) n —COR with n being an integer from 0 to 2. 
   
   
       50 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       51 . The phenolic compound O-α-glucoside according to  claim 42 , wherein R1 is a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a bicyclic or tricyclic fused ring together with the ortho carbon of R1, and said ring may be interrupted by at least one heteroatom. 
   
   
       52 . The phenolic compound O-α-glucoside according to  claim 42 , wherein said O-α-glucosyl residue is a glucose monomer. 
   
   
       53 . The phenolic compound O-α-glucoside according to  claim 42 , having a 20 fold higher solubility than the corresponding aglycone in the same physiological conditions. 
   
   
       54 . The phenolic compound O-α-glucoside according to  claim 42 , wherein said phenolic compound O-α-glucoside can be cleaved by an enzyme to release the corresponding aglycone. 
   
   
       55 . A pharmaceutical or cosmetic composition comprising a phenolic compound O-α-glucoside according to  claim 42 . 
   
   
       56 . A method for treating or preventing a cancer, a cardiovascular disease, a bacterial infection, a UVB-induced erythema, an allergy, an inflammatory or immune disorder in a subject, comprising administering to the subject an efficient amount of a phenolic compound O-α-glucoside according to  claim 42 .