Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative, Leishmanicidal and Anti-Inflammatory Properties

Molecules

José M. Padrón¹  Elena M. Sánchez-Fernández²  Carmen Ortiz Mellet²  José M. García Fernández³  Francisco Gamarro⁴  Raquel García-Hernández⁴  Manuel Aguilar-Diosdado⁵  Ana I. Arroba⁵ 

[1] BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain;Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Profesor García González 1, 41012 Seville, Spain;Instituto de Investigaciones Químicas, CSIC-University of Seville, Américo Vespucio 49, 41092 Sevilla, Spain;Instituto de Parasitología y Biomedicina “López-Neyra”, Parque Tecnológico de Ciencias de la Salud, 18016 Granada, Spain;Research Unit, Biomedical Research and Innovation Institute of Cádiz, Puerta del Mar University Hospital, Av/Ana de Viya 21, 11009 Cádiz, Spain;

关键词: seleno-sp²-iminoglycolipids;    multitarget;    immunomodulation;    cancer;    Leishmania;    inflammation;   

DOI  :  10.3390/molecules26247501

来源: DOAJ

【 摘 要 】

sp²-Iminosugar glycolipids (sp²-IGLs) represent a consolidated family of glycoconjugate mimetics encompassing a monosaccharide-like glycone moiety with a pseudoamide-type nitrogen replacing the endocyclic oxygen atom of carbohydrates and an axially-oriented lipid chain anchored at the pseudoanomeric position. The combination of these structural features makes them promising candidates for the treatment of a variety of conditions, spanning from cancer and inflammatory disorders to parasite infections. The exacerbated anomeric effect associated to the putative sp²-hybridized N-atom imparts chemical and enzymatic stability to sp²-IGLs and warrants total α-anomeric stereoselectivity in the key glycoconjugation step. A variety of O-, N-, C- and S-pseudoglycosides, differing in glycone configurational patterns and lipid nature, have been previously prepared and evaluated. Here we expand the chemical space of sp²-IGLs by reporting the synthesis of α-d-gluco-configured analogs with a bicyclic (5N,6O-oxomethylidene)nojirimycin (ONJ) core incorporating selenium at the glycosidic position. Structure–activity relationship studies in three different scenarios, namely cancer, Leishmaniasis and inflammation, convey that the therapeutic potential of the sp²-IGLs is highly dependent, not only on the length of the lipid chain (linear aliphatic C₁₂ vs. C₈), but also on the nature of the glycosidic atom (nitrogen vs. sulfur vs. selenium). The ensemble of results highlights the α-dodecylseleno-ONJ-glycoside as a promising multitarget drug candidate.

【 授权许可】

Unknown