Investigation of phenylpropanoid sucrose esters as antidiabetic compounds

• Main Author: Wong, Kathy Pooi Wen
• Other Authors: Zaher Judeh
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Chemistry
• Online Access: https://hdl.handle.net/10356/137379
• Institution: Nanyang Technological University

With a rapid increase in the number of diabetic patients, treatment of the disease has been a growing concern worldwide. Hence, research on diabetes has also been one of focus areas in the research arena. Alpha glucosidase inhibitors (AGIs) are a class of anti-diabetic drug known for their effectiveness and safety. However, they are associated with gastrointestinal (GI) side-effects such as diarrhoea, nausea and flatulence. Therefore, the key focus of this thesis is to develop phenylpropanoid sucrose esters (PSEs) as potential AGIs that are effective in controlling blood glucose levels while minimising the GI side-effects. In this thesis, three series of di-substituted PSEs were synthesized and their structure-activity relationship (SAR) studies were performed to understand the effect of the substitution pattern on the inhibition activities. Additionally, selected PSEs were tested for anti-oxidant activity, stability, permeation through the gut, and cytotoxicity. Gathering from the in-vitro tests, the caffeoyl substituent seemed to be most effective substituent in inhibiting alpha glucosidase since all the di-caffeoyl PSEs exhibited inhibitory activities against alpha glucosidase. However, none of the substituents seemed to be more potent than the other in the inhibition of alpha amylase. Although none of the di-substituted series were more potent than the other in the inhibition of alpha glucosidase, 3,6’-di-substituted PSEs were the least potent amongst the di-substituted PSEs and 3,4’-di-substituted PSEs were the most potent in the inhibition of alpha amylase. While all the tested PSE compounds degraded instantaneously when exposed to simulated gastric fluid (SGF) as expected, a trend was identified regarding the stability of the PSE compounds in simulated intestinal fluid (SIF). Di-substituted PSEs, with substituents at the O-6’ primary position and O-3 position were more susceptible to the enzymatic degradation in SIF than PSEs with substituents at O-3’ secondary position and O-3 position. However, this observation was not applicable to PSEs with methoxy group(s) attached to the substituents. Based on the DPPH and ABTS assays, the anti-oxidant abilities of the di-substituted PSEs abided the following order, hybrid 77 (hybrid of coumaroyl and feruloyl) < di-feruloyl PSEs < di-sinapoyl PSEs < di-caffeoyl PSEs. Therefore, while serving as an AGIs, the two PSE lead compounds 3,6’-caff 163 and hybrid 77 could possibly multifunction as an anti-oxidant. As observed from the Caco-2 transportation studies, hybrid 77 is systemic (Papp of 7.16±0.76 [·10-6cm/s]) while 3,6’-caff 163 is non-systemic. Not only could hybrid 77 help to regulate postprandial blood glucose, it can co-serve as an anti-oxidant once it is absorbed into the bloodstream. Furthermore, the two lead compounds did not seem to have any toxicity effect on Caco-2 cells as shown from the live/dead assay. From the MTT assay, no cytotoxicity of HepG2 cells was observed during the first 24 hours of exposure to the two lead compounds (of two different concentrations). Further exposure of MTT cells to hybrid 77 (at a higher concentration) for 48 hours, resulted in a cytotoxicity of 11%. Since hybrid 77 is a systemic drug, dosing of the compound would have to account for both the rate at which it is transported across the gut wall and its toxicity. Whereas for 3,6’-caff 163, dosing of the drug would have to take into account the rate at which it is metabolised in the small intestine. The two lead compounds exhibited different stability and permeability properties and both of them could co-serve as anti-oxidants. Overall, the work in this thesis present a basic understanding of inhibition activities, antioxidant activities, stability, absorption and cytotoxicity. Based on these results, suitable formulations and dosing of these compounds could be designed for future in-vivo tests.