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Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New Β-Gal and Gcase Inhibitors

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Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New Β-Gal and Gcase Inhibitors molecules Article Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors Maria Giulia Davighi 1, Francesca Clemente 1, Camilla Matassini 1,* , Amelia Morrone 2 , Andrea Goti 1,3, Macarena Martínez-Bailén 4 and Francesca Cardona 1,3,* 1 Department of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy; mariagiulia.davighi@unifi.it (M.G.D.); francesca.clemente@unifi.it (F.C.); andrea.goti@unifi.it (A.G.) 2 Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital and Department of Neurosciences, Pharmacology and Child Health, University of Florence, Viale Pieraccini 24, 50139 Firenze, Italy; amelia.morrone@unifi.it 3 Associated with Consorzio Interuniversitario Nazionale di Ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), 70100 Bari, Italy 4 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, García González 1, E-41012 Sevilla, Spain; [email protected] * Correspondence: camilla.matassini@unifi.it (C.M.); francesca.cardona@unifi.it (F.C.); Tel.: +39-055-457-3536 (C.M.); +39-055-457-3504 (F.C.) Academic Editors: Ivo Piantanida, René Csuk, Claus Jacob and Adegboyega K. Oyelere Received: 30 July 2020; Accepted: 30 September 2020; Published: 2 October 2020 Abstract: Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors. Keywords: synthesis; azasugars; iminosugars; lithium acetylides; lysosomal enzyme inhibitors; lysosomal storage disorders (LSDs); lysosomal sphingolipidoses; Gaucher disease 1. Introduction Lysosomal storage disorders (LSDs) are a group of more than 70 inherited orphan diseases caused by specific mutations in genes encoding lysosomal enzymes and characterized by progressive accumulation of substrates within the lysosomes, leading to organ dysfunctions [1–4]. Defective activity of lysosomal β-galactosidase (β-Gal), which is responsible for the hydrolytic removal of a terminal β-galactose residue from several glycoconjugates, leads to two different types Molecules 2020, 25, 4526; doi:10.3390/molecules25194526 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 24 Defective activity of lysosomal β-galactosidase (β-Gal), which is responsible for the hydrolytic removal of a terminal β-galactose residue from several glycoconjugates, leads to two different types of rare LSDs, the sphingolipidosis GM1-gangliosidosis and the mucopolysaccharidosis IVB (MPS IVB, also known as Morquio disease type B) [5,6]. Typical substrates of β-Gal are GM1-gangliosides, glycoproteins, oligosaccharides, and glycosaminoglycan keratan sulfate, which accumulate inside the lysosomes due to the malfunctioning enzyme, which usually presents a mutation in its natural amino Moleculesacid sequence.2020, 25, 4526To date, no pharmacological treatment is available for these severe diseases. 2 of 23 Pharmacological chaperone therapy (PCT) is emerging as a promising therapeutic approach for the treatment of LSDs, especially for those that cannot be treated with enzyme replacement therapy of(ERT). rare PCT LSDs, is thebased sphingolipidosis on pharmacological GM1-gangliosidosis chaperones (PCs), and small the mucopolysaccharidosismolecules that can selectively IVB (MPS bind IVB,mutant also enzymes known asin Morquio the endoplasmi diseasec type reticulum B) [5,6]. (ER) Typical and substrates stabilize their of β-Gal correct are GM1-gangliosides,three-dimensional glycoproteins,conformation when oligosaccharides, used at subi andnhibitory glycosaminoglycan concentrations, keratan thus improving sulfate, which lysosomal accumulate trafficking inside and the lysosomesrescuing enzymatic due to the activity. malfunctioning PCs are reversible enzyme, which inhibitors usually and presents can be replaced a mutation by the in itsnatural natural substrate amino acidof the sequence. enzyme Toinside date, nothe pharmacologicallysosomes. Their treatment main pros is available include fororal these admi severenistration, diseases. broad body distributionPharmacological (PCs have chaperone the potential therapy to cross (PCT) the isbl emergingood–brain as barrier), a promising and mino therapeuticr side effects approach [7–11]. for the treatmentNitrogen-containing of LSDs, especially glycomimetics, for those such that cannotas iminosugars be treated with(carbohydrates enzyme replacement analogues therapywith a (ERT).nitrogen PCT atom is based replacing on pharmacological the endocyclic chaperonesoxygen), ar (PCs),e the most small investigated molecules that class can of selectively PCs for LSDs bind mutant[12,13]. enzymes in the endoplasmic reticulum (ER) and stabilize their correct three-dimensional conformationRecently, whenthe first used commercially at subinhibitory available concentrations, PC for treating thus improvinglysosomal Fabry lysosomal disease, traffi Galafoldcking andTM rescuing(1-deoxygalactonojirimycin, enzymatic activity. PCs DGJ, are 1 reversible, Figure 1), inhibitors has been and marketed can be replaced in Europe by the[14]. natural Previous substrate studies of thehave enzyme shown inside that the the lysosomes.N-alkylated Their derivative main pros of DGJ include N-nonyl-DGJ oral administration, (2, Figure broad1) is able body to distribution rescue the (PCsintracellular have the activity potential of mutant to cross β the-Gal blood–brain in GM1-gangliosidosis barrier), and patient minor sidefibroblasts, effects [thus7–11 highlighting]. the potentialNitrogen-containing of PC therapy for glycomimetics, patients with such brain as iminosugars pathologies (carbohydrates [15,16]. In addition, analogues several with azasugars, a nitrogen atomcarbohydrate replacing analogues the endocyclic in which oxygen), nitrogen are the formally most investigated replaces the class anomeric of PCs for carbon, LSDs [12have,13]. shown TM interestingRecently, biological the first activities, commercially as recently available reviewed PC for by treating Simone lysosomal and coworkers Fabry [17]. disease, Galafold (1-deoxygalactonojirimycin,In particular, 4-epi-isofagomine DGJ, 1, Figure (3, Figure1), has 1) been showed marketed moderate in Europe inhibition [ 14].Previous of human studies lysosomal have shownβ-Gal (IC that50 the= 1 NµM)-alkylated [18]. Introduction derivative of of DGJ an alkylN-nonyl-DGJ chain as (in2, compounds Figure1) is able 4 and to rescue 5 (Figure the intracellular1) enhanced activitythe inhibitory of mutant potencyβ-Gal up in to GM1-gangliosidosis IC50 = 10 and IC50 = patient0.4 nM, fibroblasts,respectively. thus These highlighting compounds the were potential able ofto PCrescue therapy mutant for β patients-Gal activity with brainin fibroblasts pathologies from [15 GM1-gang,16]. In addition,liosidosis several patients azasugars, [19,20]. Moreover, carbohydrate the analogues“all-cis” trihydroxypiperidines in which nitrogen formally 6 and replaces 7 (Figure the anomeric1) were carbon,able to haveincrease shown β-Gal interesting activity biological in GM1 activities,gangliosidosis as recently patient reviewed fibroblasts by up Simone to 2–6 and fold coworkers [21]. [17]. FigureFigure 1.1. Structures ofof aa generalgeneral ββ-galactoside andand ofof somesome imino-imino- andand azasugarsazasugars inhibitorsinhibitors ofof ββ-Gal.-Gal. InA commonly particular, 4-employedepi-isofagomine strategy ( 3for, Figure the design1) showed of a potential moderate PC inhibition is to modify of humana natural lysosomal inhibitor βof-Gal the (ICcompromised50 = 1 µM) [ 18enzyme]. Introduction with the ofaim an of alkyl increasing chain as its in efficacy compounds and 4selectivity.and 5 (Figure However,1) enhanced since thethe inhibitoryinhibitory potencypotency upof a to synthetic IC50 = 10 analogue and IC50 does= 0.4 not nM, always respectively. correlate These with compounds its performance were ableas a toPC, rescue a reliable mutant structure-activityβ-Gal activity relationship in fibroblasts (SARs) from for GM1-gangliosidosis PCs is not easy and patients needs to [19 be,20 demonstrated]. Moreover, theby experimental “all-cis” trihydroxypiperidines evidence [21]. 6 and 7 (Figure1) were able to increase β-Gal activity in
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