Synthesis of 3-deoxy-3-thio-beta-d-galactopyranosyl-(1-4)-beta-d-glucopyranoside as substrate and inhibitor of TcTS

UHRIG, MARÍA LAURA; MORRONE-POZZUTO, PABLO; AGUSTI, ROSALÍA

San Martín

Simposio; 3rd Argentinian Symposium on Glycobiology; 2019

Universidad Nacional de San Martín

T. cruzi trans-sialidase (TcTS) transfer sialic acid from host glycoconjugates to terminal β-D-Galp residues on the parasite?s mucin-type glycoproteins, generating α-Neu5Ac-(23)-β-D-Galp units. TcTS shows two distinct active sites, one for the interaction with the sialic acid (donor site) and the other with the β-D-Galp in acceptor molecule (acceptor site). It represents the only route by which the protozoan can incorporate sialic acid, thus constituting a key target for the chemotherapeutic agents development. Herein we report the synthesis of benzyl 3-deoxy-3-thio-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside, a lactose analogue with ?SH in C-3 of the galactose unit. The synthetic strategy consisted in the double inversion of the C-3? of a lactose glycoside. Thus, benzyl β-lactoside was treated with Bu2SnO followed with p- PMBCl to regioselectively protect the 3-OH of the galactose. Then, the disaccharide was orthogonally protected by 4?,6?-benzylidation and benzoylation of the remaining hydroxyl groups. For the double inversion, the PMB substituent was removed with DDQ, substituted with trifluoromethanesulphonate which was later displaced with NaNO2, rendering the 3?-OH with the inverse configuration. Re-substitution of this last OH with triflate and displacement with potassium thioacetate produced the 3´-SAc with the reestablished galacto configuration. After deprotection, the acceptor and inhibitory activities toward TcTS of the benzyl 3?-SH-β-lactoside were studied.