Computational Mechanistic Studies in the Synthesis of Polyhydroxylated Lactones Obtained from a D-Erythrosyl 1,3-Dioxane Template

• Main Author: Rocha, Juliana Ferreira
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2017
• Subjects: Artificial intelligence; Bioassays; Biochemistry; Biology; Carbohydrates; Carbon; Chemical bonds; Chemistry; Diabetes; Disease; Energy; Enzymes; Genetic algorithms; Glucose; Hydrogen bonds; Lactose; Medicine; Molecular biology; Physics; Public health; Quantum physics; Small intestine
• ISBN: 9798381351651

Over time, the interest in studying molecular systems using computational methods has increased. These methods allowed to interpret and organize experimental results in order to solve or suggest new procedures to respond to a certain problem.Synthesis of polyhydroxylated sugar-like compounds is difficult for organic chemists due to the necessary stereo- and regio- selectivity in the reactions. Monosaccharides are commonly employed as starting materials, but a multistep protection/deprotection manipulations are big disadvantage issues. The D-erythrose has been known for a long time but the poor chiral induction offered by this template prevent its large use in these types of reaction. Recently it was possible to obtain, a derivative of D-erythrose, the D-erythrosyl 5-lactone, that showed total facial selectivity in 1,3-dipolar cycloadditions and nucleophilic additions.Two types of sugar-like scaffolds (five- and six-membered lactones ring) are readily accessed from nucleophilic attack to D-erythrosyl 5-lactone template. Both templates are obtained through a stereo- and regio-selective synthetic route and from which five- and six-membered lactones are obtained. Theoretical and computational means revealed that the reactions leading to both lactones share a common pathway but diverge after the second nucleophilic attack that is also the rate-limiting step in one of the reactions. The synthesis of five-membered lactone requires the presence of hard- nucleophiles and the full pathway requires 4 steps. The six-membered lactones require the presence of soft-nucleophiles and full catalytic process requires only 1 step. The origin of the stereo-selectivity is justified by an intrinsic characteristic of D-erythrosyl 5- lactone that forces the nucleophilic attack to occur only at one face of the lactone. The regio-selectivity is dependent on the nature of the attacking molecule, i.e, if hard or soft nucleophiles are used in the reactions.The inhibitory activity of D-erythrose derivatives (five- and six-membered lactones) were tested against a-glucosidase, B-glucosidase, a-galactosidase and -galactosidase. The biological assay revealed that some of the tested compounds present high specificity for some of these enzymes, an important feature in the development of new drugs targeting glycosidases.Molecular docking studies with human-enzymes were also carried out to study the origin of the specificity of some of these compounds to these enzymes. The results indicate that the factor that plays a major role in the inhibitory activity of the D- erythrose derivatives is the position of the sugar-like moiety inside the binding pocket. When an efficient interaction is obtained with this part of the molecule and the active site of the enzyme, the compounds present satisfactory inhibitory activity otherwise, they are inactive. In a-glucosidase and f-galactosidase, this sort of interaction is possible with some of the tested compounds and these are the only ones that present inhibitory activity. In B-glucosidase and a-galactosidase all the compounds are inactive because the active site is located at the bottom of the binding pocket and none of the compounds can interact with it with sugar-like moiety.