Combined Chemical, Biological and Theoretical DFT-QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts

• Published in: European journal of organic chemistry Vol. 2012; no. 28; pp. 5498 - 5514
• Main Authors: Šafář, Peter, Žúžiová, Jozefína, Marchalín, Štefan, Prónayová, Nadežda, Švorc, Ľubomír, Vrábel, Viktor, Šesták, Sergej, Rendić, Dubravko, Tognetti, Vincent, Joubert, Laurent, Daïch, Adam
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.10.2012; WILEY‐VCH Verlag; Wiley; Wiley-VCH; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Biological activity; Chemical Sciences; Chemistry; Chemistry, Organic; Conformation analysis; Density functional calculations; Enzyme inhibitors; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Natural products; Nitrogen heterocycles; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Conformation analysis; SWAINSONINE ANALOGS; ALPHA-D-MANNOSIDASE; Density functional calculations; Biological activity; Enzyme inhibitors; ASYMMETRIC TOTAL SYNTHESES; Nitrogen heterocycles; DIASTEREOSELECTIVE SYNTHESIS; Natural products; SULFONIUM SULFATE STRUCTURE; POLYHYDROXYLATED INDOLIZIDINES; SYNTHETIC METHODS; NATURAL OCCURRENCE; INDOLE ALKALOIDS; CONFORMATIONAL-ANALYSIS; Quaternization; Nitrogen heterocycle; Insecta; Epimer; Conformational analysis; Selectivity; Tetrahydrofurane; Ring cleavage; Indolizidine derivative; Inhibition; Chemical synthesis; Human; Regioselectivity; Enzyme; Theoretical study; Enzyme inhibitor; pH effect; Natural compound; Drosophilidae; Glycosylases; Arthropoda; Glycosidases; α-Mannosidase; Density functional method; Hydrolases; Invertebrata; Drosophila melanogaster; Diptera; Conformation
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201200431

Six novel enantiopure epimeric indolizidinediols have been easily prepared in high yields by an effective and well‐established regioselective THF ring‐opening reaction as a key step. Quarternization of these species was also studied and comparison was made to the quaternizations of other substituted indolizidines. Importantly, a combined theoretical DFT‐QTAIM study has cast light on the various factors that explain the observed conformational selectivity. The inhibitory properties of the six synthesized indolizidines were then investigated against the recombinant Golgi α‐mannosidase‐IIb (dGMIIb) and lysosomal α‐mannosidase (dLM408), human homologues of Drosophila melanogaster. Among the tested compounds, two of them, 4a and 4b, exhibited a pH‐dependent inhibition of dGMIIb at the milimolar level (IC50 = 3.5 or 1.7 mM at pH 5.8 or 6.5, respectively) without affecting the activity of dLM408. Six novel enantiopure indolizidinediols have been synthesized with regioselective THF ring opening as a key step. These substrates and others were then quaternized. The stereochemistry of these reactions was elucidated by NMR, X‐ray diffraction, and a combined DFT‐QTAIM study. Inhibitory assays were performed with six indolizidines and two derivatives exhibited pH‐dependent inhibition of dGMIIb.