Preparación, aplicaciones y reactividad de nuevos derivados de iminoazúcaresSíntesis de análogos del FK866 con propiedades anticáncer

Abstract

In this PhD Thesis, novel L-fuco-configurated (pyrrolidin-2-yl)-C-triazoles have been synthesized using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC) between an alkynyl-iminocyclitol and a set of commercial and synthetic azides. The derivatives obtained through parallel synthesis have been in situ assayed for their inhibitory activity towards α-fucosidases, avoiding the tedious isolation/purification steps of the individual compounds. The new derivatives were selective inhibitors of α-fucosidases in the nanomolar range, being the compounds containing the triazole moiety directly linked to C-2 of the pyrrolidine skeleton and incorporating an aromatic moiety in the triazole ring, the best of the serie. In addition, novel polyhydroxylated pyrrolizidine derivatives have been synthesized using “click” reactions. Their inhibitory activities towards glycosidases have been studied, showing the effect of the configuration and type of substitution at C-6 on glycosidase inhibition. This approach has allowed the identification of a lead compound with interesting properties as α-galactosidase inhibitor. A library of 1,4-iminocyclitol derivatives containing the amine-phosphine function has been prepared starting from commercial carbohydrates. These compounds have been used as catalysts in the [3+2] cycloaddition between alkyl allenoates and electron-deficient imines, affording 2,5-substituted-3-pyrrolines with a moderate enantioselectivity. The possibility of using the phosphine catalyst in both enantiomeric forms has allowed to obtain the corresponding enantiomeric 3-pyrrolines with similar yields, diastereo- and enantioselectivities. Furthermore, a preliminary study concerning the application of phosphine and phosphite derived iminosugars as P,N ligands in Pd-allylic substitution reactions and P,O ligands in asymmetric Ir-hydrogenation of minimally functionalized olefins has been performed. The results obtained are promising, achieving excellent enantioselectivities for most of the substrates used. Additionally, the asymmetric synthesis of bicyclic δ-lactones has been achieved through a chiral isothiourea-catalyzed Michael-Michael-Lactonisation (MML) cascade reaction, using enone-malonates and α,β-unsaturated acid chlorides as substrates. The in situ ringopening of the lactones thus obtained has afforded the corresponding stable 1,2,3,4- substituted cyclopentanes with complete stereointegrity. Finally, novel anticancer FK866 analogues have been synthesized. These compounds incorporate one or two fluorine or chlorine atoms at the pyridine moiety in order to minimize the in vivo N-oxidation of the pyridine ring present in FK866 and improve its bioavailability. In addition, differently functionalized acyl groups have been attached to the piperidine nitrogen in order to increase the diversity and establish structure-activity relationships. The anticancer activity of the new compounds has been evaluated towards several pancreas cancer cell lines. Some fluorinated derivatives have showed higher antiproliferative activity and lower citotoxicity than FK866.