Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis (original) (raw)
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Tetrahedron Letters, 2014
1-C-Alkyl iminogalactitol derivatives are highly desirable target compounds as potential pharmacological chaperones for the treatment of galactosidase-linked lysosomal storage disorders (LSDs). The synthesis of such compounds from D-galactose by a C-1 chain extension process by way of an open-chain 6-amino D-gulo nonulose intermediate was complicated by unexpected deoxygenation reactions leading to 3-deoxy iminogalactitol derivatives and epimers; an alternative, stereocontrolled synthesis from an L-tagatose derivative by C-6 chain-extension was therefore developed, which involved addition of organometallic reagents onto t-butanesulfinylimine intermediates in the key step.
European journal of medicinal chemistry, 2016
This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant β-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell l...
ACS Medicinal Chemistry Letters, 2019
Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost D-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.
Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors
Beilstein Journal of Organic Chemistry, 2010
N-Alkylation at the ring nitrogen of the D-galactosidase inhibitor 1-deoxygalactonojirimycin with a functionalised C 6 alkyl chain followed by modification with different aromatic substituents provided lipophilic 1-deoxygalactonojirimycin derivatives which exhibit inhibitory properties against β-glycosidases from E. coli and Agrobacterium sp. as well as green coffee bean α-galactosidase. In preliminary studies, these compounds also showed potential as chemical chaperones for GM1-gangliosidosis related β-galactosidase mutants.
European Journal of Medicinal Chemistry
Ganglioside GM3, belonging to glycosphingolipid family, has been known as tumor-associated carbohydrate antigen on several types of tumor. Many studies have revealed that GM3 plays a role in cell proliferation, adhesion and differentiation, which is crucial in the process of cancer development. In the present study, we firstly synthesized novel mannose containing GM3 analogues by enzymatic hydrolysis and chemical procedures. Then the antiproliferative activity of the novel analogues along with galactose containing analogues we prepared previously was investigated and the data demonstrated that these analogues exhibited antiproliferative effect on K562 and HCT116 cells. Finally, the influence of these analogues on tumor cell migration was studied on B16, B16-F10 and HCCLM3 cells by wound healing test, because the migration of tumor cells represents one of the relevant factors in assessing the malignancy of cancer. This study could lay the foundation for optimizing leading compounds and provide valuable information for finding new antitumor drugs for cancer therapy.
2020
Ganglioside GM3 is well known as a tumor-associated carbohydrate antigen on several types of tumors. Many studies have demonstrated that GM3 plays roles in cells proliferation, adhesion, motility and differentiation, which is involved in the process of cancer development. In the present study, we developed methods to synthesize GM3 analogues conveniently. By enzymatic hydrolysis and chemical procedures, two novel analogues and two known analogues were synthesized, containing lactose and glucosamine. Then anti-proliferation and anti-migration activities were evaluated by cytotoxicity assays and wound healing tests, and the data demonstrated that these analogues exhibited anticancer activities. Based on our previous studies, the structure-activity relationships were discussed. This study could provide valuable sight to find new antitumor agents for cancer therapy.
2014
An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a–f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-a-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the c-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b–f. Iminosugars 8a–f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be a-galactosidase inhibitors while 8d and 8e were selective and moderate a-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a–f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.
The Journal of Organic Chemistry, 2012
The Jocic−Reeve and Corey−Link type reaction of dichloromethyllithium with suitably protected 5-ketohexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a−c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a−c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the 1 H NMR studies, the conformations of 2a/2b were assigned as 4 C 1 and that of 2c as 1 C 4 . The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural D-gluco-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with K i and IC 50 values in the nanomolar concentration range. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies. A dx.doi.org/10.1021/jo3009534 | J. Org. Chem. XXXX, XXX, XXX−XXX H 1a 2.92 (dd) 2.63 (dd) 2.90 (dd) J 1a,1e = 14.8 Hz J 1a,1e = 12.0 Hz J 1a,1e = 13.5 Hz J 1a,2e = 3.0 Hz J 1a,2a =12.0 Hz J 1a,2e = 4.1 Hz H 1e 3.01 (dd) 2.95 (dd) 2.98 (dd) J 1e,1a = 14.8 Hz J 1e,1a = 12.0 Hz J 1e,1a = 13.5 Hz J 1e,2e = 1.7 Hz J 1e,2a = 4.0 Hz J 1e,2e = 7.1 Hz . Conformations of 2a, 2b and 2c.