The Synthesis of the Glycopolymers Containing Pendant D,L-Xylaric and L-Tartaric Moieties and Their Inhibition Behavior on the β-Glucuronidase Activity

Abstract

New styrene derivatives having D,L-xylaric and L-tartaric moieties, N-p-vinylbenzyl-D,L-xylaramic and N-p-vinylbenzyl-Ltartaramic acids (VB-D,L-XylarH 10 and VB-L-TartaH 11), were synthesized by the ring-opening reaction of 2,3,4-tri-Oacetyl-meso-xylaric anhydride and 2,3-di-O-acetyl-L-tartaric anhydride with p-vinylbenzylamine, respectively, and their subsequent hydrolysis under basic condition. The glycomonomers were copolymerized with acrylamide (AAm) to give novel polymers having xylaric and tartaric moieties in the pendants (P(VB-D,L-XylarH-co-AAm) 12 and P(VB-L-TartaH-co-AAm) 13) respectively. The inhibition abilities of the resulting glycopolymers on the -glucuronidase activity were found to be much higher than not only that of the corresponding saccharic acids but also that of the glycomonomers, especially at the lower concentration of saccharic unit by the spectrophotometry. However, the inhibition values were lower than those of the glycopolymers bearing D-glucaric pendant, P(VB-6-D-GlucaH-co-AAm) (5) and P(VB-1-D-GlucaH-co-AAm) (6), reported in our previous work. The Lineweaver-Burk plot suggested that the glycopolymer 13 and the corresponding monomer 11 inhibit the -glucuronidase activity noncompetitively, whereas the inhibition behavior of glycopolymer 12 and monomer 10 is more complicated, probably a mix-type of uncompetitive and noncompetitive ones. These are in contrast to the competitive inhibition in the presence of the glycopolymer 5 and its monomer 1.

Synthesis of glycopolymers bearing mannaric pendants as inhibitors on the β‐glucuronidase activity: The inhibition mechanisms of mannaric‐ and glucaric‐compounds

“…The glycopolymer, P(VB‐ D ‐ManaH‐ co ‐AAm) ( 10 ), was synthesized from VB‐ D ‐ManaH ( 8 ) and AAm was found to inhibit the β‐glucuronidase activity more efficiently then the corresponding monomer, 8 , and D ‐MDL ( 9 ), especially at the lower saccharic unit concentration. This result is caused by the cluster effect which is the same as those in the cases of other glycopolymers shown in our previous articles 10, 14–16. Additionally, the inhibition ability of P(VB‐ D ‐ManaH‐ co ‐AAm) ( 10 ) was almost as same as that of P(VB‐6‐ D ‐GlcaH‐ co ‐AAm) ( 1 ) that was one of effective inhibitors.…”

“…Therefore, the absence of the carboxy group in P(VB‐6‐ D ‐Glco‐ co ‐AAm) ( 3 ) and P(VB‐1‐ D ‐Glco‐ co ‐AAm) ( 4 ) should be a major occasion for their low inhibition ability. Moreover, in our another previous work,10 the inhibition ability of the glycopolymers was found to be lower in the order of 1 , P(VB‐ D , L ‐XylaH‐ co ‐AAm) ( 6 ), and P(VB‐ L ‐TartH‐ co ‐AAm) ( 7 ). …”

“…Several types of inhibitors such as amino acids,7 metal ions,8 and saccharic acids9, 10 have been investigated for β‐glucuronidase. Among them, D ‐glucaric derivatives are the most effective inhibitor for β‐glucuronidase 7, 9, 10. However, even if the saccharic derivatives were administered orally, most of them would not be carried to the intestine because of their low‐molecular weight.…”

“…However, even if the saccharic derivatives were administered orally, most of them would not be carried to the intestine because of their low‐molecular weight. Therefore, the exclusive transport of the inhibitors into the intestine is important for clinical research on their activity in the human body 10–16…”

Complexes of Glucarolactones with Water-Soluble Copolymers of N-Vinylpyrrolidone with N-Vinylamine as Inhibitors of β-Glucuronidase Efficacy

“…To reach the long-lasting inhibitory effect of lactones, it is necessary to develop their drug formulations with prolonged action. One approach to the creation of prolonged-action drugs is modifying these substances with polymers [ 5 , 35 ].…”