Rauthu, Subhash Rao (2011) Design of selective ligands for conjugate drug targeting to human serum albumin (HSA) through cysteine-34 and β-D-galactopyranoside inhibitors towards galectins. PhD thesis, Concordia University.
- Accepted Version
Galectins are a large family of 15 structurally related β-D-galactopyranoside recognizing proteins. In mammals, they play a crucial role in the control of cell differentiation, proliferation, activation, metastasis and apoptosis of immune cells. Moreover, galectins have recently shown their role in HIV-1 biology by stabilizing the viral adhesion and augmentation in virus replication. Consequently, access to potent and selective inhibitors of galectins is highly desirable as tools for detailed evaluation of galectin function and activities at the cellular level and they would constitute lead compounds for the development of galectin blocking drugs. Natural ligands have low affinities and being too polar would not pass through the cell membrane. To circumvent the above issues we have logically designed and synthesized stable C-galactoside triazole derivatives. Some of these compounds exhibit IC50 values of 2.5 mM against Galectin-3. To further improve their efficacy, we have designed and synthesized S-galactosides, C-lactosides, S-lactosides and LacNAc derivatives with a hydrophobic pharmacophoric part i.e. substituted triazole moiety through a peptide link at the anomeric position that can balance the partition coefficient to cross cell membranes and increase the in vivo stability. Biological evaluations of these compounds are in progress.
Peptides are well known for recognizing and activating specific receptors. Peptidase quickly intercepts and cleaves to transform them in to biologically inactive fragments that are further cleared by the kidneys. As a consequence peptides have a short half-life and brief duration of activity, such issues preclude them from being developed in to commercialized drugs. To overcome such issues taking advantage of the characteristic nature of HSA to accumulate in tumour tissues is exploited for transport and to increase the bioavailability. We have designed and synthesized hetero trifunctional linkers (maleimido, vinylsulphonamide and acrylamide) with a Michael acceptor on one side to conjugate with the HSA through cysteine-34, and a carboxylic acid and alkyne functionality on the other side to couple peptide based drugs and to install a better triazole derivative functionality to fit the linker in the hydrophobic binding pocket of cysteine-34. The relative reactivities of these linkers were evaluated using cysteine under physiological conditions with time, the maleimido derivative found to be the fastest reacting Michael acceptor (less than 10 min) and the vinyl sulfonamide which reacts completely within 45 min. The acrylamide functionality did not react at all under physiological conditions, requiring the pH to be raised to 8.5 for reaction to occur. Theses three linkers are under further evaluation to react with HSA under physiological conditions using HPLC and MS-FAB characterization.
|Divisions:||Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry|
|Item Type:||Thesis (PhD)|
|Authors:||Rauthu, Subhash Rao|
|Degree Name:||Ph. D.|
|Thesis Supervisor(s):||Roy, Rene and Wilds, Christopher J|
|Deposited By:||SUBHASH RAUTHU|
|Deposited On:||20 Jun 2012 17:58|
|Last Modified:||20 Jun 2012 17:58|
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