Repository logo

Browsing by Author "Garcia, Sara Cristina Nobre"

Now showing 1 - 1 of 1
  • Iminosugar-steroid conjugates as potenctial a-glycosidase inhibitors and antiproliferative agents
    Publication . Garcia, Sara Cristina Nobre; Mellet, Carmen Ortiz; Silvestre, Samuel Martins
    Steroidal conjugates are actually used in biological, medicinal or supramolecular chemistry, being a target of interest in the design and synthesis of new compounds. A large class of these conjugates are the steroidal glycosides, which includes structurally and biologically diverse semi-synthetic and natural molecules, isolated from a wide variety of both plant and animal species. Another important group of steroid conjugates is formed by steroids and alkaloids. Interestingly, several alkaloids are also glycomimetics, and includes iminosugars such as 1-deoxynojirimycin, and castanospermine. These polyhydroxylated natural and synthetic alkaloids present ability to inhibit glycosidases and have high interest, once they can be used as biological tools in studies concerning glycoconjugates function, targeting and turnover, and as potential therapeutic agents in the treatment of infections, cancer, and metabolic diseases, such as type II diabetes mellitus (DM). Among these, nojirimycin is a D-glucose mimetic and is a selective glucosidase inhibitor, however lacks anomeric selectivity for one type of glucosidases (a or ß). To improve this feature one family of glycomimetics with an endocyclic nitrogen with higher sp2 hybridation character (sp2 iminosugars) was developed based on 1-desoxynojirimycin structure, which has high selectivity for a-glucosidases. Furthermore, it was proposed that the incorporation of axially orientated substituents on pseudoanomeric position can be an important factor in aglycon-based modulation of inhibitory activity and in permeability through biologic membranes. In this context, several new sp2-iminosugar-steroid conjugates were successfully synthesised by the hybridization of a sp2-derivative of 1-desoxynojirimycin and a sterol moiety. These compounds were tested as glycosidase inhibitors, revealing a general high selectivity for a-glucosidases. In addition, a cell proliferation assay through the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method revealed that, in general, the combination of the two molecules did not lead to an improved cytotoxic effect in comparison with the isolated mother compounds. In addition, it was performed molecular docking studies in order to predict the binding energies and possible interactions with acetylcholinesterase (AcCHE), once it was noticed that dual a-glucosidase and AcCHE inhibitors can be very useful agents on the treatment of type II DM and Alzheimer Disease. The study revealed these compounds can aslo be potential AcCHE inhibition.
    2016-7-5Master thesis Open access Show more