Synthesis of polyfluoroalkyl sp2-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies

Eur J Med Chem. 2019 Nov 15:182:111604. doi: 10.1016/j.ejmech.2019.111604.

Elena M Sánchez-Fernández ¹, Ma Isabel García-Moreno ², Ana I Arroba ³, Manuel Aguilar-Diosdado ⁴, José M Padrón ⁵, Raquel García-Hernández ⁶, Francisco Gamarro ⁶, Santos Fustero ⁷, José-Emilio Sánchez-Aparicio ⁸, Laura Masgrau ⁸, José Manuel García Fernández ⁹, Carmen Ortiz Mellet ¹⁰

Affiliations

1 Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012, Seville, Spain. Electronic address: esanchez4@us.es.
2 Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012, Seville, Spain.
3 Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Av/ Ana de Viya 21, 11009, Cádiz, Spain; Research Unit, Jerez University Hospital, Carretera Circunvalación s/n, 11407, Jerez de la Frontera, Spain. Electronic address: ana.arroba@inibica.es.
4 Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Av/ Ana de Viya 21, 11009, Cádiz, Spain; Research Unit, Jerez University Hospital, Carretera Circunvalación s/n, 11407, Jerez de la Frontera, Spain.
5 BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de la Laguna, PO BOX 456, 38200, La Laguna, Spain.
6 Instituto de Parasitología y Biomedicina "López Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, 18016, Granada, Spain.
7 Department of Organic Chemistry, Universidad de Valencia, 46100, Burjassot, Spain.
8 Department of Chemistry, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
9 Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, C/ Américo Vespucio 49, Isla de la Cartuja, 41092, Sevilla, Spain.
10 Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012, Seville, Spain. Electronic address: mellet@us.es.

PMID: 31425910 DOI: 10.1016/j.ejmech.2019.111604

Abstract

Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from Cancer and Infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and anti-inflammatory mediators that antagonize each Other and negatively affect the immune response. The synthesis of analogues with narrower cytokine secretion-inducing capabilities is hampered by the intrinsic difficulty at controlling the stereochemical outcome in glycosidation reactions, particularly if targeting the α-anomer, which seriously hampers drug optimization strategies. Here we show that replacing the monosaccharide glycone by a sp²-iminosugar glycomimetic moiety allows accessing N-linked sp²-iminosugar glycolipids (sp²-IGLs) with total α-stereocontrol in a single step with no need of protecting groups or glycosidation promotors. The lipid tail has been then readily tailored by incorporating polyfluoroalkyl segments of varied lengths in view of favouring binding to the lipid binding site of the master p38 mitogen activated protein kinase (p38 MAPK), thereby polarizing the immune response in a cell-context dependent manner. The compounds have been evaluated for their antiproliferative, anti-leishmanial and anti-inflammatory activities in different cell assays. The size of the fluorous segment was found to be critical for the biological activity, probably by regulating the aggregation and membrane-crossing properties, whereas the hydroxylation profile (gluco or galacto-like) was less relevant. Biochemical and computational data further support a mechanism of action implying binding to the allosteric lipid binding site of p38 MAPK and subsequent activation of the noncanonical autophosphorylation route. The ensemble of results provide a proof of concept of the potential of sp²-IGLs as immunoregulators.

Keywords

Cancer; Immunomodulation; Inflammation; Leishmaniasis; Polyfluoroalkyl compounds; p38α MAPK; sp(2)-Iminosugar glycolipids.

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