Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2
Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and comp...
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container_title | ChemMedChem |
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creator | Gu, Xingxian Gupta, Vijayalaxmi Yang, Yan Zhu, Jin‐Yi Carlson, Erick J. Kingsley, Carolyn Tash, Joseph S. Schönbrunn, Ernst Hawkinson, Jon Georg, Gunda I. |
description | Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.
β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development. |
doi_str_mv | 10.1002/cmdc.201700558 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5725710</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1973296590</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4688-389c0a15447550c775dbfe092fa279f3cfe4d011f4984af91037536be20166bb3</originalsourceid><addsrcrecordid>eNqFUcGO0zAQtRCIXRauHJElLnBosZ04tjkgpS0si5aCVDhbjuPsukrjYjuF3PYTkPgI_mu_BGe7FDhxsGY08-bN-D0AHmM0xQiRF3pT6ylBmCFEKb8DjjEv0IRhzu4eciaOwIMQ1gjlOcf8PjgiXDDKMDkGP1fR9zr23lxf_Sh1tDsbB7iKfW1NgK6By-ur77M-Dm2KOL3auG9D59bW282gbQefLWepvFi-ew7LTrXuojfhJVzYoN3O-GHk-Oii6SJUXQ1XpjXjFgPLje2cHnTrtqlpo2vhWXdpq5T5m82nsxLfzKSEPAT3GtUG8-g2noDPb15_mr-dnH84PZuX5xOdF5xPMi40UpjmOaMUacZoXTUGCdIowkST6cbkNcK4yQXPVSMwyhjNisokCYuiqrIT8GrPu-2rjal1Os2rVm7Tb5UfpFNW_tvp7KW8cDtJGUmKokTw9JbAuy9JiijXrvdJmCCxYBkRBRUjarpHae9C8KY5bMBIjsbK0Vh5MDYNPPn7rgP8t5MJIPaAr7Y1w3_o5Pz9Yv6H_BevZLaV</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1973296590</pqid></control><display><type>article</type><title>Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2</title><source>MEDLINE</source><source>Wiley Blackwell Journals</source><creator>Gu, Xingxian ; Gupta, Vijayalaxmi ; Yang, Yan ; Zhu, Jin‐Yi ; Carlson, Erick J. ; Kingsley, Carolyn ; Tash, Joseph S. ; Schönbrunn, Ernst ; Hawkinson, Jon ; Georg, Gunda I.</creator><creatorcontrib>Gu, Xingxian ; Gupta, Vijayalaxmi ; Yang, Yan ; Zhu, Jin‐Yi ; Carlson, Erick J. ; Kingsley, Carolyn ; Tash, Joseph S. ; Schönbrunn, Ernst ; Hawkinson, Jon ; Georg, Gunda I.</creatorcontrib><description>Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.
β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201700558</identifier><identifier>PMID: 28975712</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>1-Deoxynojirimycin - analogs & derivatives ; 1-Deoxynojirimycin - chemistry ; 1-Deoxynojirimycin - pharmacology ; Amino Alcohols - chemistry ; Amino Alcohols - pharmacology ; aminocyclitols ; Analogs ; beta-Glucosidase - antagonists & inhibitors ; beta-Glucosidase - metabolism ; Ceramide ; Cyclopentane ; Cyclopentanes - chemistry ; Cyclopentanes - pharmacology ; Dose-Response Relationship, Drug ; Drug Discovery ; enzyme inhibition ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Glucosyltransferase ; Humans ; Inhibition ; Inhibitors ; lysosomal glucosidase 1 ; Molecular Conformation ; N-butyl-1-deoxynojirimycin ; Nitrogen ; non-lysosomal glucosidase 2 ; Stereochemistry ; Structure-Activity Relationship ; Substitutes</subject><ispartof>ChemMedChem, 2017-12, Vol.12 (23), p.1977-1984</ispartof><rights>2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.</rights><rights>2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4688-389c0a15447550c775dbfe092fa279f3cfe4d011f4984af91037536be20166bb3</citedby><cites>FETCH-LOGICAL-c4688-389c0a15447550c775dbfe092fa279f3cfe4d011f4984af91037536be20166bb3</cites><orcidid>0000-0003-0288-384X ; 0000-0001-5461-7071 ; 0000-0001-8564-7345 ; 0000-0001-9074-1571 ; 0000-0001-5407-7458 ; 0000-0001-8915-3393 ; 0000-0001-5436-4262 ; 0000-0002-3589-3510 ; 0000-0002-8900-9460 ; 0000-0002-9514-727X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201700558$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201700558$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,782,786,887,1419,27931,27932,45581,45582</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28975712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gu, Xingxian</creatorcontrib><creatorcontrib>Gupta, Vijayalaxmi</creatorcontrib><creatorcontrib>Yang, Yan</creatorcontrib><creatorcontrib>Zhu, Jin‐Yi</creatorcontrib><creatorcontrib>Carlson, Erick J.</creatorcontrib><creatorcontrib>Kingsley, Carolyn</creatorcontrib><creatorcontrib>Tash, Joseph S.</creatorcontrib><creatorcontrib>Schönbrunn, Ernst</creatorcontrib><creatorcontrib>Hawkinson, Jon</creatorcontrib><creatorcontrib>Georg, Gunda I.</creatorcontrib><title>Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.
β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</description><subject>1-Deoxynojirimycin - analogs & derivatives</subject><subject>1-Deoxynojirimycin - chemistry</subject><subject>1-Deoxynojirimycin - pharmacology</subject><subject>Amino Alcohols - chemistry</subject><subject>Amino Alcohols - pharmacology</subject><subject>aminocyclitols</subject><subject>Analogs</subject><subject>beta-Glucosidase - antagonists & inhibitors</subject><subject>beta-Glucosidase - metabolism</subject><subject>Ceramide</subject><subject>Cyclopentane</subject><subject>Cyclopentanes - chemistry</subject><subject>Cyclopentanes - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>enzyme inhibition</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glucosyltransferase</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>lysosomal glucosidase 1</subject><subject>Molecular Conformation</subject><subject>N-butyl-1-deoxynojirimycin</subject><subject>Nitrogen</subject><subject>non-lysosomal glucosidase 2</subject><subject>Stereochemistry</subject><subject>Structure-Activity Relationship</subject><subject>Substitutes</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNqFUcGO0zAQtRCIXRauHJElLnBosZ04tjkgpS0si5aCVDhbjuPsukrjYjuF3PYTkPgI_mu_BGe7FDhxsGY08-bN-D0AHmM0xQiRF3pT6ylBmCFEKb8DjjEv0IRhzu4eciaOwIMQ1gjlOcf8PjgiXDDKMDkGP1fR9zr23lxf_Sh1tDsbB7iKfW1NgK6By-ur77M-Dm2KOL3auG9D59bW282gbQefLWepvFi-ew7LTrXuojfhJVzYoN3O-GHk-Oii6SJUXQ1XpjXjFgPLje2cHnTrtqlpo2vhWXdpq5T5m82nsxLfzKSEPAT3GtUG8-g2noDPb15_mr-dnH84PZuX5xOdF5xPMi40UpjmOaMUacZoXTUGCdIowkST6cbkNcK4yQXPVSMwyhjNisokCYuiqrIT8GrPu-2rjal1Os2rVm7Tb5UfpFNW_tvp7KW8cDtJGUmKokTw9JbAuy9JiijXrvdJmCCxYBkRBRUjarpHae9C8KY5bMBIjsbK0Vh5MDYNPPn7rgP8t5MJIPaAr7Y1w3_o5Pz9Yv6H_BevZLaV</recordid><startdate>20171207</startdate><enddate>20171207</enddate><creator>Gu, Xingxian</creator><creator>Gupta, Vijayalaxmi</creator><creator>Yang, Yan</creator><creator>Zhu, Jin‐Yi</creator><creator>Carlson, Erick J.</creator><creator>Kingsley, Carolyn</creator><creator>Tash, Joseph S.</creator><creator>Schönbrunn, Ernst</creator><creator>Hawkinson, Jon</creator><creator>Georg, Gunda I.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0288-384X</orcidid><orcidid>https://orcid.org/0000-0001-5461-7071</orcidid><orcidid>https://orcid.org/0000-0001-8564-7345</orcidid><orcidid>https://orcid.org/0000-0001-9074-1571</orcidid><orcidid>https://orcid.org/0000-0001-5407-7458</orcidid><orcidid>https://orcid.org/0000-0001-8915-3393</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3589-3510</orcidid><orcidid>https://orcid.org/0000-0002-8900-9460</orcidid><orcidid>https://orcid.org/0000-0002-9514-727X</orcidid></search><sort><creationdate>20171207</creationdate><title>Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2</title><author>Gu, Xingxian ; Gupta, Vijayalaxmi ; Yang, Yan ; Zhu, Jin‐Yi ; Carlson, Erick J. ; Kingsley, Carolyn ; Tash, Joseph S. ; Schönbrunn, Ernst ; Hawkinson, Jon ; Georg, Gunda I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4688-389c0a15447550c775dbfe092fa279f3cfe4d011f4984af91037536be20166bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Deoxynojirimycin - analogs & derivatives</topic><topic>1-Deoxynojirimycin - chemistry</topic><topic>1-Deoxynojirimycin - pharmacology</topic><topic>Amino Alcohols - chemistry</topic><topic>Amino Alcohols - pharmacology</topic><topic>aminocyclitols</topic><topic>Analogs</topic><topic>beta-Glucosidase - antagonists & inhibitors</topic><topic>beta-Glucosidase - metabolism</topic><topic>Ceramide</topic><topic>Cyclopentane</topic><topic>Cyclopentanes - chemistry</topic><topic>Cyclopentanes - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>enzyme inhibition</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glucosyltransferase</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>lysosomal glucosidase 1</topic><topic>Molecular Conformation</topic><topic>N-butyl-1-deoxynojirimycin</topic><topic>Nitrogen</topic><topic>non-lysosomal glucosidase 2</topic><topic>Stereochemistry</topic><topic>Structure-Activity Relationship</topic><topic>Substitutes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gu, Xingxian</creatorcontrib><creatorcontrib>Gupta, Vijayalaxmi</creatorcontrib><creatorcontrib>Yang, Yan</creatorcontrib><creatorcontrib>Zhu, Jin‐Yi</creatorcontrib><creatorcontrib>Carlson, Erick J.</creatorcontrib><creatorcontrib>Kingsley, Carolyn</creatorcontrib><creatorcontrib>Tash, Joseph S.</creatorcontrib><creatorcontrib>Schönbrunn, Ernst</creatorcontrib><creatorcontrib>Hawkinson, Jon</creatorcontrib><creatorcontrib>Georg, Gunda I.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gu, Xingxian</au><au>Gupta, Vijayalaxmi</au><au>Yang, Yan</au><au>Zhu, Jin‐Yi</au><au>Carlson, Erick J.</au><au>Kingsley, Carolyn</au><au>Tash, Joseph S.</au><au>Schönbrunn, Ernst</au><au>Hawkinson, Jon</au><au>Georg, Gunda I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2017-12-07</date><risdate>2017</risdate><volume>12</volume><issue>23</issue><spage>1977</spage><epage>1984</epage><pages>1977-1984</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.
β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28975712</pmid><doi>10.1002/cmdc.201700558</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-0288-384X</orcidid><orcidid>https://orcid.org/0000-0001-5461-7071</orcidid><orcidid>https://orcid.org/0000-0001-8564-7345</orcidid><orcidid>https://orcid.org/0000-0001-9074-1571</orcidid><orcidid>https://orcid.org/0000-0001-5407-7458</orcidid><orcidid>https://orcid.org/0000-0001-8915-3393</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3589-3510</orcidid><orcidid>https://orcid.org/0000-0002-8900-9460</orcidid><orcidid>https://orcid.org/0000-0002-9514-727X</orcidid><oa>free_for_read</oa></addata></record> |
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recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5725710 |
source | MEDLINE; Wiley Blackwell Journals |
subjects | 1-Deoxynojirimycin - analogs & derivatives 1-Deoxynojirimycin - chemistry 1-Deoxynojirimycin - pharmacology Amino Alcohols - chemistry Amino Alcohols - pharmacology aminocyclitols Analogs beta-Glucosidase - antagonists & inhibitors beta-Glucosidase - metabolism Ceramide Cyclopentane Cyclopentanes - chemistry Cyclopentanes - pharmacology Dose-Response Relationship, Drug Drug Discovery enzyme inhibition Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Glucosyltransferase Humans Inhibition Inhibitors lysosomal glucosidase 1 Molecular Conformation N-butyl-1-deoxynojirimycin Nitrogen non-lysosomal glucosidase 2 Stereochemistry Structure-Activity Relationship Substitutes |
title | Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-06T15%3A19%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structure%E2%80%93Activity%20Studies%20of%20N%E2%80%90Butyl%E2%80%901%E2%80%90deoxynojirimycin%20(NB%E2%80%90DNJ)%20Analogues:%20Discovery%20of%20Potent%20and%20Selective%20Aminocyclopentitol%20Inhibitors%20of%20GBA1%20and%20GBA2&rft.jtitle=ChemMedChem&rft.au=Gu,%20Xingxian&rft.date=2017-12-07&rft.volume=12&rft.issue=23&rft.spage=1977&rft.epage=1984&rft.pages=1977-1984&rft.issn=1860-7179&rft.eissn=1860-7187&rft_id=info:doi/10.1002/cmdc.201700558&rft_dat=%3Cproquest_pubme%3E1973296590%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1973296590&rft_id=info:pmid/28975712&rfr_iscdi=true |