Design, Synthesis, and Anticancer Activity of a Selenium-Containing Galectin-3 and Galectin-9N Inhibitor

Abstract

Galectins are soluble β-D-galactoside-binding proteins whose implication in cancer progression and disease outcome makes them prominent targets for therapeutic intervention. In this frame, the development of small inhibitors that block selectively the activity of galectins represents an important strategy for cancer therapy which is, however, still relatively underdeveloped. To this end, we designed here a rationally and efficiently novel diglycosylated compound, characterized by a selenoglycoside bond and the presence of a lipophilic benzyl group at both saccharide residues. The relatively high binding affinity of the new compound to the carbohydrate recognition domain of two galectins, galectin 3 and galectin 9, its good antiproliferative and anti-migration activity towards melanoma cells, as well as its anti-angiogenesis properties, pave the way for its further development as an anticancer agent.

Exploring the Molecular Interactions of Symmetrical and Unsymmetrical Selenoglycosides with Human Galectin-1 and Galectin-3

“…The expression and purification of Gal-3 CRD (amino acid residues 112–250) was carried out as described in Di Gaetano et al, 2022 [ 10 ]. The choice of the extension of the construct is dictated by the crystallization conditions reported in the literature.…”

“…The replacement of the oxygen atom with a sulfur in TDG had already led to improvements in the enzymatic/hydrolytic stability, electing TDG as a starting scaffold for further derivatives. Successively, the introduction of selenium as the bridging atom in place of sulfur created a new version of diglycosylated analogues characterized by a selenoglycoside bond between two galactose units (SeDG) [ 9 , 10 ]. This modification proved to be a winning move not only because selenium has been incorporated into carbohydrates to assist in X-ray crystal structure determination using single/multiple wavelength anomalous diffraction techniques [ 11 ] and in NMR studies [ 12 ] but mainly due to its enhanced protease stability and its inherent antioxidant and peroxidant properties [ 10 ].…”

“…Successively, the introduction of selenium as the bridging atom in place of sulfur created a new version of diglycosylated analogues characterized by a selenoglycoside bond between two galactose units (SeDG) [ 9 , 10 ]. This modification proved to be a winning move not only because selenium has been incorporated into carbohydrates to assist in X-ray crystal structure determination using single/multiple wavelength anomalous diffraction techniques [ 11 ] and in NMR studies [ 12 ] but mainly due to its enhanced protease stability and its inherent antioxidant and peroxidant properties [ 10 ]. Furthermore, we have recently featured a new version of SeDG, introducing a lipophilic benzyl group at C-3 of both sugar residues [ 10 ] that was revealed to bind both Gal-3 CRD and Gal-9N CRD and showed anti-proliferative and anti-migration effects on a melanoma cell line and anti-angiogenesis activities.…”

“…This modification proved to be a winning move not only because selenium has been incorporated into carbohydrates to assist in X-ray crystal structure determination using single/multiple wavelength anomalous diffraction techniques [ 11 ] and in NMR studies [ 12 ] but mainly due to its enhanced protease stability and its inherent antioxidant and peroxidant properties [ 10 ]. Furthermore, we have recently featured a new version of SeDG, introducing a lipophilic benzyl group at C-3 of both sugar residues [ 10 ] that was revealed to bind both Gal-3 CRD and Gal-9N CRD and showed anti-proliferative and anti-migration effects on a melanoma cell line and anti-angiogenesis activities. Its relatively high affinity and its anti-migration and anti-angiogenesis properties pave the way for further development of such compounds as anti-tumor agents.…”

Human Galectin-9 Promotes the Expansion of HIV Reservoirs in vivo in Humanized Mice

“…Endogenous Gal-9 is highly abundant in vivo, especially during HIV infection [5] , and its sustained levels have been associated, during ART-suppressed HIV infection, with the state of chronic inflammation and immune activation that is central to the development of several HIVassociated co-morbidities [25][26][27][28][29][30][31][32] . Therefore, clarifying the mechanistic underpinnings of the overall adverse effects of elevated Gal-9 during ART-suppressed HIV infection may lead to the development of interventions to target Gal-9 (such as anti-Gal-9 antibodies and small molecule inhibitors targeting Gal-9 [33][34][35] ) to improve immune functionality, reduce inflammationassociated co-morbidities, and reduce levels of HIV persistence, in the setting of viral suppression by ART. The mean and standard mean of error (SEM) are displayed.…”