Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines
Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of...
Saved in:
| Published in | Journal of organic chemistry Vol. 81; no. 23; pp. 11726 - 11733 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
02.12.2016
|
| Subjects | |
| Online Access | Get full text |
Cover
Loading…
| Abstract | Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors. |
|---|---|
| AbstractList | Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors. |
| Author | Houk, K. N Krenske, Elizabeth H Petter, Russell C |
| AuthorAffiliation | The University of Queensland Department of Chemistry and Biochemistry University of California School of Chemistry and Molecular Biosciences Celgene Avilomics Research |
| AuthorAffiliation_xml | – name: University of California – name: School of Chemistry and Molecular Biosciences – name: Celgene Avilomics Research – name: The University of Queensland – name: Department of Chemistry and Biochemistry |
| Author_xml | – sequence: 1 givenname: Elizabeth H surname: Krenske fullname: Krenske, Elizabeth H email: e.krenske@uq.edu.au – sequence: 2 givenname: Russell C surname: Petter fullname: Petter, Russell C – sequence: 3 givenname: K. N surname: Houk fullname: Houk, K. N email: houk@chem.ucla.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27934455$$D View this record in MEDLINE/PubMed |
| BookMark | eNp1kcFvFCEYxYmpsdvq2ZvhaGJmywDDzHiru602tjEx9Txh4KNLMwMrMJvs_-QfKeOs3uRCgN97jy_vAp057wChtyVZl4SWV1LF9bNXa9HnU9O8QKuyoqQQLeFnaEUIpQWjgp2jixifSV5VVb1C57RuGedVtUK_vloHyaqIpdP4cQdh9Pro5DhfeYO_wwFCtP0A-dH6AV9rbZP1LuLk8YN3vvij3Fqpkj3IBBo_WLWTkFGlYJ98iB_x3bgfrJKL0PiA0w7wFqJ9cnPKNkxPMQfIhD_Z7LbxBzmAS8NxTtkcY4L8zfgavTRyiPDmtF-iH7c3j5svxf23z3eb6_tCMsZSAYz1QktZc0UUF7VoFed9Hl1yoetKK1GZUquWN4YQpQhttTSmNY2ipqQg2CV6v_jug_85QUzdaKOCYZAO_BS7suF10_JWzOjVgqrgYwxgun2wowzHriTdXFGXK-pyRd2poqx4dzKf-hH0P_5vJxn4sACLcgouz_pfu9_P_qE- |
| CitedBy_id | crossref_primary_10_4018_IJKDB_2017070104 crossref_primary_10_4018_IJKDB_2017070103 crossref_primary_10_1016_j_bioorg_2018_11_001 crossref_primary_10_4018_IJKDB_2017070102 crossref_primary_10_1002_ejoc_201701785 crossref_primary_10_1039_C8OB00397A crossref_primary_10_1002_cbic_202000700 crossref_primary_10_1002_anie_202217895 crossref_primary_10_1021_acs_joc_1c01335 crossref_primary_10_1002_anie_202206938 crossref_primary_10_1016_j_cej_2023_144563 crossref_primary_10_1039_D2OB02262A crossref_primary_10_1002_anie_201909803 crossref_primary_10_1021_acs_jpcb_3c04710 crossref_primary_10_1039_C9PY01260E crossref_primary_10_1039_D1CC06765F crossref_primary_10_1016_j_drudis_2018_01_035 crossref_primary_10_1016_j_ejmech_2019_111771 crossref_primary_10_1021_acsearthspacechem_9b00278 crossref_primary_10_1080_17460441_2021_1892640 crossref_primary_10_1021_jacs_8b03704 crossref_primary_10_1002_qua_26768 crossref_primary_10_1002_anie_201912902 crossref_primary_10_1039_D1PY00198A crossref_primary_10_1002_ange_202206938 crossref_primary_10_1002_ange_201909803 crossref_primary_10_1021_acsami_3c11288 crossref_primary_10_1016_j_ejmech_2020_112836 crossref_primary_10_1016_j_bbapap_2017_05_009 crossref_primary_10_1021_acs_chemrev_1c00014 crossref_primary_10_3390_molecules25102406 crossref_primary_10_1021_acs_joc_1c00349 crossref_primary_10_1021_acs_jcim_1c00897 crossref_primary_10_1002_slct_201903640 crossref_primary_10_1021_acsmacrolett_3c00717 crossref_primary_10_1039_D0CC06313D crossref_primary_10_1021_acs_jcim_9b00404 crossref_primary_10_1039_D2OB01656G crossref_primary_10_1039_C9OB02709B crossref_primary_10_1002_ange_201807760 crossref_primary_10_1016_j_tips_2020_10_005 crossref_primary_10_1021_acs_jmedchem_9b00387 crossref_primary_10_1039_D0OB00726A crossref_primary_10_1002_ange_202217895 crossref_primary_10_1021_acs_joc_8b02677 crossref_primary_10_1016_j_bbrc_2020_09_038 crossref_primary_10_1002_slct_202204350 crossref_primary_10_1021_acs_orglett_7b00588 crossref_primary_10_3390_polym14204457 crossref_primary_10_1016_j_redox_2023_102856 crossref_primary_10_1016_j_ejmech_2018_12_002 crossref_primary_10_1039_D3CC05015G crossref_primary_10_1021_acscombsci_7b00169 crossref_primary_10_1007_s00706_018_2175_1 crossref_primary_10_1002_slct_201803497 crossref_primary_10_1002_ange_201912902 crossref_primary_10_4155_fmc_2023_0034 crossref_primary_10_1038_s41598_022_17685_z crossref_primary_10_1021_acs_joc_9b00850 crossref_primary_10_1021_acs_joc_9b03055 crossref_primary_10_1021_jacs_2c02185 crossref_primary_10_1021_acs_analchem_0c01881 crossref_primary_10_1021_acs_jctc_4c00290 crossref_primary_10_1021_acs_jcim_3c00720 crossref_primary_10_1039_D0SC00605J crossref_primary_10_1111_tra_12802 crossref_primary_10_1002_anie_202201168 crossref_primary_10_3390_ph15111366 crossref_primary_10_1021_acs_macromol_1c01049 crossref_primary_10_1021_acs_jmedchem_8b01153 crossref_primary_10_1002_hlca_202300020 crossref_primary_10_1002_anie_201807760 crossref_primary_10_1021_acs_orglett_1c04282 crossref_primary_10_3390_ijms25116099 crossref_primary_10_1126_science_adi5009 crossref_primary_10_1021_acs_analchem_0c03418 crossref_primary_10_1002_ange_202201168 crossref_primary_10_3390_appliedchem3020016 crossref_primary_10_1021_acs_orglett_7b00720 crossref_primary_10_1039_D0SC04960C crossref_primary_10_1021_acs_jcim_4c00366 crossref_primary_10_1016_j_ccr_2023_215321 crossref_primary_10_1021_acsmacrolett_4c00333 crossref_primary_10_1039_C9OB00324J crossref_primary_10_1016_j_bioorg_2020_104036 crossref_primary_10_1038_s41598_020_72491_9 crossref_primary_10_1021_acs_macromol_0c00335 crossref_primary_10_1007_s11101_020_09700_w crossref_primary_10_1021_acs_chemrestox_9b00385 crossref_primary_10_1021_acs_jnatprod_7b00745 crossref_primary_10_1021_jacs_3c03643 crossref_primary_10_3390_ph16040547 crossref_primary_10_1021_acs_orglett_3c04160 crossref_primary_10_3390_antiox11081485 crossref_primary_10_1021_acs_macromol_2c00603 crossref_primary_10_1039_C7SC02805A crossref_primary_10_1002_wcms_1636 crossref_primary_10_1002_slct_202203048 crossref_primary_10_1021_acscatal_3c03538 crossref_primary_10_1002_slct_202204138 |
| Cites_doi | 10.1039/b810189b 10.1139/v68-127 10.1002/jcc.10189 10.1021/ct400773k 10.1016/S1470-2045(13)70604-1 10.1007/s40265-013-0170-8 10.1007/s40265-015-0533-4 10.1021/np100826q 10.1021/ja505194w 10.1039/j29710002335 10.1021/jacs.6b03052 10.1002/ejoc.201300358 10.1021/jp9716997 10.1016/S0040-4020(01)81304-1 10.1038/nchembio.925 10.1063/1.464304 10.1139/v68-128 10.1021/ja01068a022 10.1021/jo00797a008 10.1038/nrc3702 10.1007/s40265-015-0380-3 10.1038/bjc.2013.178 10.1002/anie.201005959 10.1200/JCO.2011.40.9433 10.2174/13895575112091330 10.1021/j100096a001 10.1063/1.477924 10.1158/2159-8290.CD-13-0314 10.1200/JCO.2012.42.7906 10.1021/jm5014659 10.1139/v64-383 10.1139/v66-347 10.1021/jm3003922 10.1002/0471264180.or025.03 10.1021/jo200761w 10.1016/j.bmcl.2005.03.031 10.1016/j.drudis.2015.05.005 10.1124/jpet.113.203489 10.1007/s10822-015-9857-0 10.1021/ja401221b 10.1007/s00214-007-0310-x 10.1021/jo8012385 10.1021/ja01094a025 10.1021/cm402180t 10.1124/pr.111.004846 10.1038/nrd3410 10.1038/nchembio.1817 10.1021/jm800498e 10.1021/jo3021709 10.1016/j.bmc.2015.04.038 10.1103/PhysRevB.37.785 10.1016/j.chembiol.2012.12.006 10.1038/nchembio.1666 10.1039/b414300k 10.1039/C5NJ00368G 10.1063/1.481224 10.1021/ol301781u 10.1055/s-2007-965968 10.1063/1.464913 |
| ContentType | Journal Article |
| Copyright | Copyright © 2016 American Chemical Society |
| Copyright_xml | – notice: Copyright © 2016 American Chemical Society |
| DBID | CGR CUY CVF ECM EIF NPM AAYXX CITATION 7X8 |
| DOI | 10.1021/acs.joc.6b02188 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed CrossRef MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) CrossRef MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Chemistry |
| EISSN | 1520-6904 |
| EndPage | 11733 |
| ExternalDocumentID | 10_1021_acs_joc_6b02188 27934455 e05532331 |
| Genre | Research Support, U.S. Gov't, Non-P.H.S Research Support, Non-U.S. Gov't Journal Article |
| GroupedDBID | - .K2 29L 53G 55A 5RE 5VS 7~N 85S AABXI ABFLS ABMVS ABPPZ ABPTK ABUCX ABUFD ACGFS ACJ ACNCT ACS AEESW AENEX AFEFF ALMA_UNASSIGNED_HOLDINGS AQSVZ BAANH CJ0 CS3 D0L DU5 DZ EBS ED ED~ EJD F20 F5P GNL IH9 IHE JG JG~ K2 LG6 P2P PZZ ROL RXW TAE TN5 UI2 UKR UPT VF5 VG9 VQA W1F WH7 X XFK YZZ --- -DZ -~X 4.4 AAHBH ABJNI ABQRX ACBEA ACGFO ADHLV AGXLV AHGAQ CGR CUPRZ CUY CVF ECM EIF GGK IH2 NPM TAF XSW YQT ZCA AAYXX CITATION 7X8 |
| ID | FETCH-LOGICAL-a333t-e33b6daa74c0c46769c44b055a46d75dc65f1dc948f00cc029daff9f8c2f12e63 |
| IEDL.DBID | ACS |
| ISSN | 0022-3263 |
| IngestDate | Sat Aug 17 01:00:38 EDT 2024 Fri Aug 23 03:28:48 EDT 2024 Sat Sep 28 08:48:06 EDT 2024 Thu Aug 27 13:43:19 EDT 2020 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 23 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-a333t-e33b6daa74c0c46769c44b055a46d75dc65f1dc948f00cc029daff9f8c2f12e63 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| PMID | 27934455 |
| PQID | 1847894966 |
| PQPubID | 23479 |
| PageCount | 8 |
| ParticipantIDs | proquest_miscellaneous_1847894966 crossref_primary_10_1021_acs_joc_6b02188 pubmed_primary_27934455 acs_journals_10_1021_acs_joc_6b02188 |
| ProviderPackageCode | JG~ 55A AABXI GNL VF5 7~N ACJ VG9 W1F ACS AEESW AFEFF .K2 ABMVS ABUCX IH9 BAANH AQSVZ ED~ UI2 |
| PublicationCentury | 2000 |
| PublicationDate | 20161202 2016-12-02 |
| PublicationDateYYYYMMDD | 2016-12-02 |
| PublicationDate_xml | – month: 12 year: 2016 text: 20161202 day: 02 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Journal of organic chemistry |
| PublicationTitleAlternate | J. Org. Chem |
| PublicationYear | 2016 |
| Publisher | American Chemical Society |
| Publisher_xml | – name: American Chemical Society |
| References | ref9/cit9 ref3/cit3 ref37/cit37b ref37/cit37a ref16/cit16 ref27/cit27a ref27/cit27b ref8/cit8 ref31/cit31 ref2/cit2 ref1/cit1a ref1/cit1c ref1/cit1b ref20/cit20 ref17/cit17 ref26/cit26b ref10/cit10 ref26/cit26a ref13/cit13 ref19/cit19a ref35/cit35a ref36/cit36 ref18/cit18 ref35/cit35d ref35/cit35c ref19/cit19b ref35/cit35b ref11/cit11 ref25/cit25 ref29/cit29 ref21/cit21b ref21/cit21c ref32/cit32 ref21/cit21a ref5/cit5 ref28/cit28 ref34/cit34b ref4/cit4a ref4/cit4b ref34/cit34a ref14/cit14a ref24/cit24b ref12/cit12 ref14/cit14c ref14/cit14b ref15/cit15 ref14/cit14e ref14/cit14d ref14/cit14g ref24/cit24a ref14/cit14f ref14/cit14i ref30/cit30a ref14/cit14h ref30/cit30c ref30/cit30b ref33/cit33 ref6/cit6a ref6/cit6b ref30/cit30e ref30/cit30d ref7/cit7 |
| References_xml | – ident: ref31/cit31 – ident: ref36/cit36 doi: 10.1039/b810189b – ident: ref26/cit26a doi: 10.1139/v68-127 – ident: ref34/cit34b doi: 10.1002/jcc.10189 – ident: ref21/cit21b doi: 10.1021/ct400773k – ident: ref4/cit4a doi: 10.1016/S1470-2045(13)70604-1 – ident: ref4/cit4b doi: 10.1007/s40265-013-0170-8 – ident: ref5/cit5 doi: 10.1007/s40265-015-0533-4 – ident: ref19/cit19b doi: 10.1021/np100826q – ident: ref16/cit16 doi: 10.1021/ja505194w – ident: ref30/cit30c doi: 10.1039/j29710002335 – ident: ref25/cit25 doi: 10.1021/jacs.6b03052 – ident: ref14/cit14h doi: 10.1002/ejoc.201300358 – ident: ref34/cit34a doi: 10.1021/jp9716997 – ident: ref14/cit14c doi: 10.1016/S0040-4020(01)81304-1 – ident: ref12/cit12 doi: 10.1038/nchembio.925 – ident: ref35/cit35b doi: 10.1063/1.464304 – ident: ref26/cit26b doi: 10.1139/v68-128 – ident: ref30/cit30a doi: 10.1021/ja01068a022 – ident: ref30/cit30d doi: 10.1021/jo00797a008 – ident: ref10/cit10 doi: 10.1038/nrc3702 – ident: ref6/cit6b doi: 10.1007/s40265-015-0380-3 – ident: ref9/cit9 doi: 10.1038/bjc.2013.178 – ident: ref14/cit14e doi: 10.1002/anie.201005959 – ident: ref7/cit7 doi: 10.1200/JCO.2011.40.9433 – ident: ref13/cit13 doi: 10.2174/13895575112091330 – ident: ref35/cit35d doi: 10.1021/j100096a001 – ident: ref37/cit37a doi: 10.1063/1.477924 – ident: ref8/cit8 doi: 10.1158/2159-8290.CD-13-0314 – ident: ref6/cit6a doi: 10.1200/JCO.2012.42.7906 – ident: ref24/cit24a doi: 10.1021/jm5014659 – ident: ref14/cit14a doi: 10.1139/v64-383 – ident: ref14/cit14b doi: 10.1139/v66-347 – ident: ref28/cit28 doi: 10.1021/jm3003922 – ident: ref27/cit27a doi: 10.1002/0471264180.or025.03 – ident: ref27/cit27b – ident: ref32/cit32 – ident: ref21/cit21a doi: 10.1021/jo200761w – ident: ref19/cit19a doi: 10.1016/j.bmcl.2005.03.031 – ident: ref1/cit1c doi: 10.1016/j.drudis.2015.05.005 – ident: ref11/cit11 doi: 10.1124/jpet.113.203489 – ident: ref21/cit21c doi: 10.1007/s10822-015-9857-0 – ident: ref17/cit17 doi: 10.1021/ja401221b – ident: ref33/cit33 doi: 10.1007/s00214-007-0310-x – ident: ref29/cit29 doi: 10.1021/jo8012385 – ident: ref30/cit30b doi: 10.1021/ja01094a025 – ident: ref30/cit30e doi: 10.1021/cm402180t – ident: ref20/cit20 doi: 10.1124/pr.111.004846 – ident: ref1/cit1a doi: 10.1038/nrd3410 – ident: ref3/cit3 doi: 10.1038/nchembio.1817 – ident: ref2/cit2 doi: 10.1021/jm800498e – ident: ref14/cit14f doi: 10.1021/jo3021709 – ident: ref24/cit24b doi: 10.1016/j.bmc.2015.04.038 – ident: ref35/cit35a doi: 10.1103/PhysRevB.37.785 – ident: ref1/cit1b doi: 10.1016/j.chembiol.2012.12.006 – ident: ref18/cit18 doi: 10.1038/nchembio.1666 – ident: ref14/cit14d doi: 10.1039/b414300k – ident: ref15/cit15 doi: 10.1039/C5NJ00368G – ident: ref37/cit37b doi: 10.1063/1.481224 – ident: ref14/cit14g doi: 10.1021/ol301781u – ident: ref14/cit14i doi: 10.1055/s-2007-965968 – ident: ref35/cit35c doi: 10.1063/1.464913 |
| SSID | ssj0000555 |
| Score | 2.539767 |
| Snippet | Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib,... |
| SourceID | proquest crossref pubmed acs |
| SourceType | Aggregation Database Index Database Publisher |
| StartPage | 11726 |
| SubjectTerms | Binding Sites Cysteine - chemistry Drug Design Kinetics Sulfhydryl Compounds - chemistry Thermodynamics |
| Title | Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines |
| URI | http://dx.doi.org/10.1021/acs.joc.6b02188 https://www.ncbi.nlm.nih.gov/pubmed/27934455 https://search.proquest.com/docview/1847894966 |
| Volume | 81 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV1Lb9QwELZKe4ALUJ4LpTJSD1yyJH5tzK3NUhUQHIBKvUXO2K4WSow2WaT2N_VHdpxkt0BVtdc8xpZn4vmi-fwNITtW20munU-k1zwRCiDBUK6STOXobhNPd8bzzp-_qIND8fFIHl2KRf9fwWfZWwPN-EeAsapiOsrvkA0W-YMRBRXfLjddKeVKGJwpvlLxuWIgpiFo_k1D12DLLsfsP-jZWU0nTRipJT_Hi7Yaw9lV4cabp_-Q3B-QJt3tQ2OTrLn6EblbLBu8PSbnnxBhRpVmampLMV7mv4LtG9Q3NHj61XWUjerE4c1ZQFPW9gQv2gaKm0FIujens3g44g-CVksHFj7dhUiXCfPmHf3wF2edIkSmCDnptCOOxFGm88VxgwOYlu7N0FoRMPYxE56cxlGKKDQdmflPyOH---_FQTI0b0gM57xNHOeVssZMBKQgIpEWhKjQTUYoO5EWlPSZBS1yn6YAKdPWeK99DsxnzCn-lKzXoXbPCeUTqDCX50paLzJttEUUozhL0UgkwY7IDq5yOXx8TdnV1VlW9hehHJZ-RN4sXV7-7qU8rn_09TIkSnRKrKGY2oUF2sZsnmuBP4kj8qyPlZUxhnudEFK-uN18XpJ7iL66Lkgp2yLr7XzhXiHCaavtLrYvAHgq95w |
| link.rule.ids | 315,786,790,2782,27109,27957,27958,57093,57143 |
| linkProvider | American Chemical Society |
| linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1Lb9QwEB6VcigX3pSlPIzUA5csSfxI3FvJUm3pQwJaqbfI8QMtlBhtskjlN_EjO06yWx6qBFcnGTueseez_M0MwLaRJsuldRF3kkZMaB2hKVdRInJUtwrRnSHe-ehYTE_ZuzN-tgbxMhYGB9GgpKa7xL_KLpC8Dm2fvR6LKnil_Abc5BmexgMYKj5e7b2c81V-8FTQVTKfvwQEb6Sb373RNRCzczV7d-D9apAdw-TLeNFWY_3jj_yN__MXd-H2gDvJbm8o92DN1vdho1iWe3sAPw8Qb4aczUTVhqD1zL9605erb4h35IPtCBzVucWHM4-ijOnpXqT1BLcGH3VfTmYhVOI7QlhDBk4-2dWBPOPnzQ7Z_4XBThAwEwSgZNLRSEIvk_niU4MdqJa8maG0wuNKQL94fhF6KULa6cDTfwine29Pimk0lHKIFKW0jSyllTBKZUzHmgVarWasQm0pJkzGjRbcJUZLlrs41jpOpVHOSZfr1CWpFfQRrNe-to-B0ExX6NlzwY1jiVTSIKYRNI1RSKDEjmAbZ7kclmJTdrfsaVL2jbocpn4Er5aaL7_1iT2uf_Xl0jJKVEq4UVG19QuUjb49lwyPjCPY7E1mJSzFnY8xzp_823hewMb05OiwPNw_PtiCW4jLuvpIcfoU1tv5wj5D7NNWzztzvwSEfQAW |
| linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1Zb9QwELagSMAL97GcRuoDL9km8bExbyXLqqVQIWClvkWOD7RtiatNFgl-Ez-SGSe7XKoEr04ydjxjz2f5mxlCtq2yk0I5nwivWMKlMQmYcp1ksgB1a4zuxHjnt4dyb85fH4mjISgMY2FgEC1IauMlPq7qM-uHDAPZDrYfBzOWNXqm4iK5JLB8NwKi8sPP_VcIsckRnku2SejzlwD0SKb93SOdAzOju5ldJ_PNQCPL5GS86uqx-fZHDsf__ZMb5NqAP-lubzA3yQXX3CJXynXZt9vk-wHgTszdTHVjKVjR8nOwfdn6lgZP37tI5KhPHTxcBBBlbU_7ol2gsEWEJH45XWDIxBeAspYO3Hy6a5BEE5btC7r_C5OdAnCmAETpNNJJsJfpcvWphQ50R18uQFoZYEWAfzz9ir2UmH4a-fp3yHz26mO5lwwlHRLNGOsSx1gtrdYTblLDkV5rOK9BY5pLOxHWSOEzaxQvfJoak-bKau-VL0zus9xJdpdsNaFx9wllE1ODhy-ksJ5nSisL2EayPAUhSI0dkW2Y5WpYkm0Vb9vzrOobTTVM_Yg8X2u_OusTfJz_6rO1dVSgFLxZ0Y0LK5ANPr5QHI6OI3KvN5uNsBx2QM6FePBv43lKLr-bzqo3-4cHD8lVgGexTFKaPyJb3XLlHgME6uon0eJ_AKaPApA |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Kinetics+and+Thermodynamics+of+Reversible+Thiol+Additions+to+Mono-+and+Diactivated+Michael+Acceptors%3A+Implications+for+the+Design+of+Drugs+That+Bind+Covalently+to+Cysteines&rft.jtitle=Journal+of+organic+chemistry&rft.au=Krenske%2C+Elizabeth+H&rft.au=Petter%2C+Russell+C&rft.au=Houk%2C+K.+N&rft.date=2016-12-02&rft.pub=American+Chemical+Society&rft.issn=0022-3263&rft.eissn=1520-6904&rft.volume=81&rft.issue=23&rft.spage=11726&rft.epage=11733&rft_id=info:doi/10.1021%2Facs.joc.6b02188&rft.externalDocID=e05532331 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0022-3263&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0022-3263&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0022-3263&client=summon |