Synthesis and Biological Evaluation of α-L-Fucosidase Inhibitors: 5a-Carba-α-L-fucopyranosylamine and Related Compounds

Abstract

Keywords: Carbohydrates / Cyclitols / Carba sugars / 5a-Carba-α--fucopyranosylamine / Enzyme inhibitors / α--Fucosidase inhibitors 5a-Carba-α-L-fucopyranosylamine (5), an α-glucosidase inhibitor validamine analog possessing an α-L-fucose-type structure, and four related compounds (4 and 6−8) were synthesized and their glycosidase inhibitory potential determined. Carbafucosylamine has already been shown to pos-

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[1] Reflecting the important roles of this carbohydrate motif, there are specific enzymes, termed a-l-fucosidases( which are part of al arger class of enzymes termedg lycoside hydrolases [2] ), that act to cleave a-l-fucose moieties from glycoconjugates. For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). [3][4][5] As with other glycoside hydrolases, a-l-fucosidases have been classified into families based upon amino acid sequence homologies, with known a-l-fucosidases falling into GH families GH29 and GH95.…”

“…This enzymatic process mediates the distribution of fucosylated glycans, and dysfunction or abnormal distribution of a-l-fucosidasesi n humans is associated with several disease states. [8] The deoxy analogue 3 [10] and pyrrolidine 4 [11] are also good inhibitors of these enzymes and compounds prepared that mimic shape such as 5 [12] and compounds such as 6, [13] developed by Vasella, which are thought to mimic the charge and shape of the transition state also display good potency.In developing new types of inhibitors for GH29 a-l-fucosidases we were drawn to the inhibitor PUGNAc [14] (Scheme 1D) which has been shown to be ah ighly potent inhibitoro f retaining b-N-acetylhexosaminidases. Due to the importance of fucosidases and glycoside hydrolases in general,e fforts have been made to understandt he function of these enzymes focusingo ns ubstrate recognition and catalytic mechanism.…”

“…For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C).…”

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[1] Reflecting the important roles of this carbohydrate motif, there are specific enzymes, termed a-l-fucosidases( which are part of al arger class of enzymes termedg lycoside hydrolases [2] ), that act to cleave a-l-fucose moieties from glycoconjugates. For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). [3][4][5] As with other glycoside hydrolases, a-l-fucosidases have been classified into families based upon amino acid sequence homologies, with known a-l-fucosidases falling into GH families GH29 and GH95.…”

“…This enzymatic process mediates the distribution of fucosylated glycans, and dysfunction or abnormal distribution of a-l-fucosidasesi n humans is associated with several disease states. [8] The deoxy analogue 3 [10] and pyrrolidine 4 [11] are also good inhibitors of these enzymes and compounds prepared that mimic shape such as 5 [12] and compounds such as 6, [13] developed by Vasella, which are thought to mimic the charge and shape of the transition state also display good potency.In developing new types of inhibitors for GH29 a-l-fucosidases we were drawn to the inhibitor PUGNAc [14] (Scheme 1D) which has been shown to be ah ighly potent inhibitoro f retaining b-N-acetylhexosaminidases. Due to the importance of fucosidases and glycoside hydrolases in general,e fforts have been made to understandt he function of these enzymes focusingo ns ubstrate recognition and catalytic mechanism.…”

“…For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C).…”

Biosynthesis and Biological Activity of Carbasugars

“…In the search for different sugar hydrolase inhibitors, 5a-carba--DL-fucopyranosyl amine [355,356] ((±)-167) and 5a-carba--L-fucopyranosylamine (168) [357] were prepared. These compounds have been shown to be strong inhibitors of -L-fucosidase.…”

Synthesis and Conformational and Biological Aspects of Carbasugars

“…5a-Carba-α- dl -fucopyranosyl amine ((±)- 116 ) and 5a-carba-β- l -fucopyranosylamine ( 117 ) were prepared and evaluated (Figure ) in the search for different sugar hydrolase inhibitors. They have displayed a very potent and specific inhibition of α- l -fucosidase (bovine kidney), with the effect of (±)- 116 being essentially comparable to that of deoxyfuconojirimicin, the most powerful mammalian α- l -fucosidase inhibitor identified.…”

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[1] Reflecting the important roles of this carbohydrate motif, there are specific enzymes, termed a-l-fucosidases( which are part of al arger class of enzymes termedg lycoside hydrolases [2] ), that act to cleave a-l-fucose moieties from glycoconjugates. For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). [3][4][5] As with other glycoside hydrolases, a-l-fucosidases have been classified into families based upon amino acid sequence homologies, with known a-l-fucosidases falling into GH families GH29 and GH95.…”

“…This enzymatic process mediates the distribution of fucosylated glycans, and dysfunction or abnormal distribution of a-l-fucosidasesi n humans is associated with several disease states. [8] The deoxy analogue 3 [10] and pyrrolidine 4 [11] are also good inhibitors of these enzymes and compounds prepared that mimic shape such as 5 [12] and compounds such as 6, [13] developed by Vasella, which are thought to mimic the charge and shape of the transition state also display good potency.In developing new types of inhibitors for GH29 a-l-fucosidases we were drawn to the inhibitor PUGNAc [14] (Scheme 1D) which has been shown to be ah ighly potent inhibitoro f retaining b-N-acetylhexosaminidases. Due to the importance of fucosidases and glycoside hydrolases in general,e fforts have been made to understandt he function of these enzymes focusingo ns ubstrate recognition and catalytic mechanism.…”

“…For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C).…”

Biosynthesis and Biological Activity of Carbasugars

“…In the search for different sugar hydrolase inhibitors, 5a-carba--DL-fucopyranosyl amine [355,356] ((±)-167) and 5a-carba--L-fucopyranosylamine (168) [357] were prepared. These compounds have been shown to be strong inhibitors of -L-fucosidase.…”

Synthesis and Conformational and Biological Aspects of Carbasugars

“…5a-Carba-α- dl -fucopyranosyl amine ((±)- 116 ) and 5a-carba-β- l -fucopyranosylamine ( 117 ) were prepared and evaluated (Figure ) in the search for different sugar hydrolase inhibitors. They have displayed a very potent and specific inhibition of α- l -fucosidase (bovine kidney), with the effect of (±)- 116 being essentially comparable to that of deoxyfuconojirimicin, the most powerful mammalian α- l -fucosidase inhibitor identified.…”

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[1] Reflecting the important roles of this carbohydrate motif, there are specific enzymes, termed a-l-fucosidases( which are part of al arger class of enzymes termedg lycoside hydrolases [2] ), that act to cleave a-l-fucose moieties from glycoconjugates. For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). [3][4][5] As with other glycoside hydrolases, a-l-fucosidases have been classified into families based upon amino acid sequence homologies, with known a-l-fucosidases falling into GH families GH29 and GH95.…”

“…This enzymatic process mediates the distribution of fucosylated glycans, and dysfunction or abnormal distribution of a-l-fucosidasesi n humans is associated with several disease states. [8] The deoxy analogue 3 [10] and pyrrolidine 4 [11] are also good inhibitors of these enzymes and compounds prepared that mimic shape such as 5 [12] and compounds such as 6, [13] developed by Vasella, which are thought to mimic the charge and shape of the transition state also display good potency.In developing new types of inhibitors for GH29 a-l-fucosidases we were drawn to the inhibitor PUGNAc [14] (Scheme 1D) which has been shown to be ah ighly potent inhibitoro f retaining b-N-acetylhexosaminidases. Due to the importance of fucosidases and glycoside hydrolases in general,e fforts have been made to understandt he function of these enzymes focusingo ns ubstrate recognition and catalytic mechanism.…”

“…For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C). For example, compounds that mimic the chargeo ft he putativet ransition state such as amines 1 [8] (and N-alkyl analogues [9] )a nd 2 [8] have been shown to be potent inhibitors of a-l-fucosidases (Scheme 1C).…”

Biosynthesis and Biological Activity of Carbasugars

“…In the search for different sugar hydrolase inhibitors, 5a-carba--DL-fucopyranosyl amine [355,356] ((±)-167) and 5a-carba--L-fucopyranosylamine (168) [357] were prepared. These compounds have been shown to be strong inhibitors of -L-fucosidase.…”

Synthesis and Conformational and Biological Aspects of Carbasugars

“…5a-Carba-α- dl -fucopyranosyl amine ((±)- 116 ) and 5a-carba-β- l -fucopyranosylamine ( 117 ) were prepared and evaluated (Figure ) in the search for different sugar hydrolase inhibitors. They have displayed a very potent and specific inhibition of α- l -fucosidase (bovine kidney), with the effect of (±)- 116 being essentially comparable to that of deoxyfuconojirimicin, the most powerful mammalian α- l -fucosidase inhibitor identified.…”