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, antiarrythmic, antithrombotic, hypocholesterolemic, antilipoperoxidant, hepatoprotective, anti-inflammatory, anticarcinogenic, antimutagenic, antineoplastic, anti-thrombotic and vasodilatory formulations, or in any other field of application.

1 . 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, or —OH 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 cannot 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 —COR or —(CH═CH) n —COR with n being an integer from 0 to 2; 
         —H; 
       
       
         
           
           
               
               
           
         
       
       and,
 a C 10 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a fused ring (bi or tricyclic) together with the ortho carbon of R1, said ring being optionally interrupted by at least one heteroatom; 
 wherein R is H or a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 10  hydrocarbon group, optionally 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, a (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, a hydroxyl (—OH), an aldehyde group (—CHO), a halogen, a (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. 
 
     
     
         2 . The method according to  claim 1 , wherein:
 a) 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; or 
         b) R1 of the phenolic compound is 
       
       
         
           
           
               
               
           
         
         wherein R7 is selected from the group consisting of H, or —OH and R8 is H or OH, with the proviso that at least one among R7 and R8 represents OH; or 
         c) 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 cannot 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; 
         d) R1 of the phenolic compound is —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR with n being an integer from 0 to 2; or 
         e) 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; or 
         f) R1 of the phenolic compound is —(CH 2 ) n —COR or —(CH═CH) n —COR with n being an integer from 0 to 2; or 
         g) R1 of the phenolic compound is H; or 
         h) R1 of the phenolic compound is 
       
       
         
           
           
               
               
           
         
       
       or
 i) R1 of the phenolic compound is 
 
       
         
           
           
               
               
           
         
       
       or
 j) R1 of the phenolic compound is 
 
       
         
           
           
               
               
           
         
       
       k) R1 of the phenolic compound is 
       
         
           
           
               
               
           
         
         or 
         l) R1 of the phenolic compound is a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a fused ring (bi or tricyclic) together with the ortho carbon of R1, said ring being optionally interrupted by at least one heteroatom; or 
         m) phenolic compound is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 2 , wherein the phenolic compound is selected from the group consisting of the taxifolin, the eriodictyol, the dihydrorobinetin and the fustin. 
     
     
         4 . The method according to  claim 2 , wherein the phenolic compound is selected in the group consisting of catechin, epicatechin, catechin gallate, epicatechin gallate, gallocatechin, epigallocatechin, and gallocatechin gallate. 
     
     
         5 . The method according to  claim 2 , wherein the phenolic compound is selected from the group consisting of rhamnetin, tfisetin, robinetin, gossypetin, orientin, homoorientin and tcirsiliol. 
     
     
         6 . The method according to  claim 2 , wherein the phenolic compound is selected from the group consisting of homoprotocatechuic acid, dihydrocaffeic acid, protocatechuic acid ethyl ester, propyl gallate, tgallic acid, hamamelitannin (2′,5-di-β-galloyl-hamamelose) and protocatechuic acid. 
     
     
         7 . The method according to  claim 2 , wherein the phenolic compound is selected from the group consisting of caffeic acid, rosmarinic acid, esculetin, 4-methylesculetin, nordalbergin (6,7-dihydroxyphenylcoumarin), chlorogenic acid, caffeic acid phenethyl ester, chicoric acid (dicaffeoyl tartaric acid), echinacoside (2-(3,4-dihydroxyphenyl)ethyl O-6-deoxy-alpha-L-mannopyranosyl-(1→3)—O—(beta-D-glucopyranosyl-(1→6))-, 4-(3-(3,4-dihydroxyphenyl)-2-propenoate), beta-D-glucopyranoside) and verbascoside. 
     
     
         8 . The method according to  claim 2 , wherein the phenolic compound is selected from the group consisting of maclurine, 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzophenone, butein (2′,3,4,4-tetrahydroxychalcone), 3,4-dihydroxyacetophenone, marein (2′,3,3′,4,4′-pentahydroxy-4′-glucosylchalcone), and eriodictyolchalcone (2′,4′,6′,3,4-pentahydroxychalcone). 
     
     
         9 . A phenolic compound O-α-glucoside having the following formula: 
       
         
           
           
               
               
           
         
         wherein 
         A and B, identical or different, are H or an α-glucosyl residue, with the proviso that at least one of A and B is an 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, or —OH 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 OCH3; R6 is H or OH, R9 is H or OH, R10 is H, OCH3 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 cannot 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 —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 fused ring (bi or tricyclic) together with the ortho carbon of R1, said ring being optionally interrupted by at least one heteroatom; 
         wherein R is H or a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 10  hydrocarbon group, optionally 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, a (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, a hydroxyl (—OH), an aldehyde group (—CHO), a halogen, a (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. 
       
     
     
         10 . The phenolic compound O-α-glucoside according to  claim 9 , wherein: 
       
         
           
           
               
               
           
         
         a) R1 is 
         and the phenolic compound O-α-glucoside is selected from the group consisting of the taxifolin O-α-glucoside, the eriodictyol O-α-glucoside, the dihydrorobinetin O-α-glucoside and the fustin O-α-glucoside; or 
         b) R1 is 
       
       
         
           
           
               
               
           
         
         and the phenolic compound O-α-glucoside is selected from the group consisting of the catechin gallate O-α-glucoside, the epicatechin gallate O-α-glucoside, the gallocatechin O-α-glucoside, the epigallocatechin O-α-glucoside, the gallocatechin gallate O-α-glucoside; or 
         c) R1 is 
       
       
         
           
           
               
               
           
         
         and the phenolic compound O-α-glucoside is selected from the group consisting of the rhamnetin O-α-glucoside, the fisetin O-α-glucoside, the robinetin O-α-glucoside, the gossypetin O-α-glucoside, the orientin O-α-glucoside, the homoorientin O-α-glucoside and the cirsiliol O-α-glucoside; or 
         d) R1 is —(CH 2 ) n —COOR or —(CH 2 ) n —CONHR with n being an integer from 0 to 2, and the phenolic compound O-α-glucoside is selected from the group consisting of the homoprotocatechuic acid O-α-glucoside, the dihydrocaffeic acid O-α-glucoside, the protocatechuic acid ethyl ester O-α-glucoside, the propyl gallate O-α-glucoside, the gallic acid O-α-glucoside, the hamamelitannin O-α-glucoside and the protocatechuic acid O-α-glucoside; or 
         e) R1 is —(CR12=CH)—COOR or —(CR12=CH)—CONHR, R12 being H or a C 1 -C 6  linear or cyclic alkyl or alkenyl and the phenolic compound O-α-glucoside is selected from the group consisting of the caffeic acid O-α-glucoside, the rosmarinic acid O-α-glucoside, the esculetin O-α-glucoside, the 4-methylesculetin O-α-glucoside, the nordalbergin (6,7-dihydroxyphenylcoumarin) O-α-glucoside, the chlorogenic acid O-α-glucoside, the caffeic acid phenethyl ester O-α-glucoside, the chicoric acid (dicaffeoyl tartaric acid) O-α-glucoside, the echinacoside (2-(3,4-dihydroxyphenyl)ethyl O-6-deoxy-alpha-L-mannopyranosyl-(1→3)—O—(beta-D-glucopyranosyl-(1→6))-, 4-(3-(3,4-dihydroxyphenyl)-2-propenoate) O-α-glucoside, beta-D-glucopyranoside O-α-glucoside and the verbascoside O-α-glucoside; or 
         f) R1 is —(CH 2 ) n —COR or —(CH═CH) n —COR with n being an integer from 0 to 2, and the phenolic compound O-α-glucoside is selected in the group consisting of the maclurine O-α-glucoside, the 3,4-dihydroxybenzaldehyde O-α-glucoside, the 3,4-dihydroxybenzophenone O-α-glucoside, the butein (2′,3,4,4′-tetrahydroxychalcone) O-α-glucoside, the 3,4-dihydroxyacetophenone O-α-glucoside, the marein (2′,3,3′,4,4′-pentahydroxy-4′-glucosylchalcone) O-α-glucoside, and the eriodictyolchalcone (2′,4′,6′,3,4-pentahydroxychalcone) O-α-glucoside; or 
         g) R1 is selected from the group consisting of H; 
       
       
         
           
           
               
               
           
         
         and the phenolic compound O-α-glucoside is selected from the group consisting of the pyrocatechol O-α-glucoside, the nordihydroguaiaretic acid O-α-glucoside, the 3-hydroxydaidzein O-α-glucoside, the oleuropein O-α-glucoside, and maritimein (3′,4′,6,7-tetrahydroxy-6-O-glucosylaurone) O-α-glucoside; or 
         h) R1 is a C 1 -C 10  hydrocarbon group which forms with the represented ring of formula (I) a fused ring (bi or tricyclic) together with the ortho carbon of R1, said ring being optionally interrupted by at least one heteroatom, and the phenolic compound O-α-glucoside is selected in the group consisting of the anthrarobin O-α-glucoside and the salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) O-α-glucoside. 
       
     
     
         11 . A pharmaceutical or cosmetic composition comprising a phenolic compound O-α-glucoside according to  claim 9 . 
     
     
         12 . 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 effective amount of phenolic compound O-α-glucoside according to  claim 9 .