Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

Author(s)

Zamoner, Luis O. B. ^[1] ; Aragao-Leoneti, Valquiria ^[1] ; Carvalho, Ivone ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto - Brazil

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 12, n. 3 SEP 2019.
• Web of Science Citations: 0

Abstract

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an S(N)2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards alpha-glucosidase with IC50 41 mu M and 138 mu M, respectively, using DNJ as reference (IC50 134 mu M). On the other hand, beta-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 mu M, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 mu M). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 mu M) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides alpha-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest beta-glucosidase inhibitors of the series with IC50 of 4 mu M. (AU)

• FAPESP's process: 07/00910-6 - Synthesis and evaluation of glucosidase inhibitors with potential anti-HIV activity
• Grantee: Valquiria Aragão Leoneti
• Support Opportunities: Scholarships in Brazil - Post-Doctoral