Feruloyl Sucrose Esters: Potent and Selective Inhibitors of α-glucosidase and α-amylase

Abstract

Introduction: Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects. Methods: Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α-amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model. Results: All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α-amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α-glucosidase than α-amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic ‘OH’ group, and the diisopropylidene bridges were key determinants of the % inhibition of α-glucosidase and α-amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic ‘OH’ groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice. Conclusion: Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.

Targeted Synthesis of 3,3′-, 3,4′- and 3,6′-Phenylpropanoid Sucrose Esters

“…The study also identified O-3 substituents as favorable for increased level of inhibition of α-glucosidase [6,9,10]. Additionally, the di-isopropylidene bridges favorably reduce the inhibition of α-amylase and minimally affect the inhibition of α-glucosidase [6,9,10]. These results were further corroborated by silico docking and molecular modelling studies.…”

“…The side effects hamper patient compliance and acceptability, and limit the wide use of these effective drugs [13]. Based on a preliminary structure-activity relationship (SAR) study [6,9,10], we demonstrated that their in vitro inhibition of α-glucosidase and α-amylase depended on the type, number, and position of the phenylpropanoid moieties on the sucrose core and the presence/absence of the di-isopropylidene bridges (Figure 1). The study also identified O-3 substituents as favorable for increased level of inhibition of α-glucosidase [6,9,10].…”

“…For example, the PSEs Lapathoside D, Lapathoside C, Hydropiperoside, Vanicoside B, and Diboside A showed variable levels of inhibitory activities against α-glucosidase and α-amylase [2][3][4][5]. Recently, we proposed PSEs as promising alpha-glucosidase inhibitors (AGIs) that have a better side effect profile than commercial AGIs [6][7][8][9][10]. AGIs possess an excellent efficacy and safety record, and are represented by the commercial drugs acarbose (the gold standard), voglibose, and miglitol.…”

“…Based on a preliminary structure-activity relationship (SAR) study [6,9,10], we demonstrated that their in vitro inhibition of α-glucosidase and α-amylase depended on the type, number, and position of the phenylpropanoid moieties on the sucrose core and the presence/absence of the di-isopropylidene bridges (Figure 1). The study also identified O-3 substituents as favorable for increased level of inhibition of α-glucosidase [6,9,10]. Additionally, the di-isopropylidene bridges favorably reduce the inhibition of α-amylase and minimally affect the inhibition of α-glucosidase [6,9,10].…”

An orthogonal approach for the precise synthesis of phenylpropanoid sucrose esters

“…This is specifically important to study the structure-activity relationships (SARs) of these compounds to develop lead drug candidates. 32 Our earlier investigation of PSEs as potential antidiabetic lead candidates proved that the type, number, and position of the (substituted) cinnamoyl moieties greatly impact the a-glucosidase and a-amylase inhibition activities. 32 In particular, the moieties at O-3, O-3 0 , O-4 0 , and O-6 0 play a critical role in the inhibition.…”