| Revision as of 01:50, 12 June 2011 edit97.93.110.39 (talk)No edit summary← Previous edit |
Latest revision as of 02:44, 3 December 2024 edit undoBoghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,966 edits consistent citation formatting |
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| ImageFile = Nutlin3.PNG |
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| Name = Nutlin 3 |
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| verifiedrevid = 433813167 |
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| ImageFile = Nutlin 3 Structure.svg |
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| IUPACName = (±)-4--piperazin-2-one <sub>Nutlin-3</sub> |
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| IUPACName = (±)-4--piperazin-2-one |
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| OtherNames = Nutlin |
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| OtherNames = Nutlin |
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| Section1 = {{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo = 548472 |
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| CASNo = 548472-68-0 |
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| CASOther = (Nutlin-3) |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| PubChem = 16755649 |
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| UNII = 53IA0V845C |
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| SMILES = CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCNC(=O)C3)C4=CC=C(C=C4)Cl)C5=CC=C(C=C5)Cl <sub>canonical</sub> |
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| PubChem = 16755649 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 191334 |
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| SMILES = CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCNC(=O)C3)C4=CC=C(C=C4)Cl)C5=CC=C(C=C5)Cl |
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| C=30|H=30|Cl=2|N=4|O=4 |
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| Formula = C<sub>30</sub>H<sub>30</sub>C<sub>l2</sub>N<sub>4</sub>O<sub>4</sub> |
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| MolarMass = 581.4896 |
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'''Nutlins''' are ''cis''-] analogs which inhibit the interaction between ] and tumour suppressor ], and were discovered by screening a chemical library by Vassilev ''et al.'' Nutlin-1, Nutlin-2 and Nutlin-3 were all identified in the same screen,<ref name="Nutlin">{{cite journal |author = Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA |title = In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 |journal=Science |volume=303 |issue= 5659|pages= 844–848 |year= 2004 |pmid= 14704432 |doi=10.1126/science.1092472}}</ref> however Nutlin-3 is the compound most commonly used in anti-cancer studies.<ref name="annrev">{{cite journal |author = Shangary S, Wang S. |title = Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy |journal = Annu Rev Pharmacol Toxicol. |volume = 49|issue = | pages = 223–241 |year = 2008 |pmid = 18834305 |doi=10.1146/annurev.pharmtox.48.113006.094723 |pmc = 2676449 }}</ref>. Inhibiting the interaction between mdm2 and p53 stabilizes p53 and is thought to selectively induce a growth-inhibiting state called ] in cancer cells. These compounds are therefore thought to work best on tumors that contain normal or wild type p53.{{Citation needed|date=April 2011}} Nutlin-3 has been shown to affect the production of p53 within minutes.<ref name="Leeuwen et al.">{{Cite journal|work=]|publisher=Landes Bioscience|title=Mechanism-specific signatures for small-molecule p53 activators|volume=10|issue=10|date=15 May 2011|authors=Ingeborg M.M. van Leeuwen, Maureen Higgins, Johanna Campbell, Christopher J. Brown, Anna R. McCarthy, Lisa Pirrie, Nicholas J. Westwood and Sonia Laín|accessdate=24 April 2011}}</ref> |
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'''Nutlins''' are ''cis''-] analogs which inhibit the interaction between ] and tumor suppressor ], and which were discovered by screening a chemical library by Vassilev ''et al.'' Nutlin-1, nutlin-2, and nutlin-3 were all identified in the same screen;<ref name="Nutlin">{{cite journal | vauthors = Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA | title = In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 | journal = Science | volume = 303 | issue = 5659 | pages = 844–848 | date = February 2004 | pmid = 14704432 | doi = 10.1126/science.1092472 | s2cid = 16132757 | bibcode = 2004Sci...303..844V }}</ref> however, Nutlin-3 is the compound most commonly used in anti-cancer studies.<ref name="annrev">{{cite journal | vauthors = Shangary S, Wang S | title = Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy | journal = Annual Review of Pharmacology and Toxicology | volume = 49 | pages = 223–241 | year = 2008 | pmid = 18834305 | pmc = 2676449 | doi = 10.1146/annurev.pharmtox.48.113006.094723 }}</ref> Nutlin small molecules occupy p53 binding pocket of MDM2 and effectively disrupt the p53–MDM2 interaction that leads to activation of the p53 pathway in p53 wild-type cells.<ref>{{cite journal | vauthors = Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT | title = Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 6 | pages = 1888–1893 | date = February 2006 | pmid = 16443686 | pmc = 1413632 | doi = 10.1073/pnas.0507493103 | doi-access = free }}</ref> Inhibiting the interaction between mdm2 and p53 stabilizes p53, and is thought to selectively induce a growth-inhibiting state called ] in cancer cells. These compounds are therefore thought to work best on tumors that contain normal or "wild-type" p53.{{Citation needed|date=April 2011}} Nutlin-3 has been shown to affect the production of p53 within minutes.<ref name="Leeuwen et al.">{{cite journal | vauthors = van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ, Laín S | title = Mechanism-specific signatures for small-molecule p53 activators | journal = Cell Cycle | volume = 10 | issue = 10 | pages = 1590–1598 | date = May 2011 | pmid = 21490429 | doi = 10.4161/cc.10.10.15519 | publisher = Landes Bioscience | doi-access = free }}</ref> |
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The more potent of the two ]s, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion.<ref>{{cite journal | vauthors = Davis TA, Johnston JN | title = Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor | journal = Chemical Science | volume = 2 | issue = 6 | pages = 1076–1079 | date = January 2011 | pmid = 22708054 | pmc = 3375951 | doi = 10.1039/C1SC00061F }}</ref> Several derivatives of nutlin, such as RG7112 and RG7388 (]) have been developed and progressed into human studies.<ref>{{cite journal | vauthors = Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, Holak TA | title = Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells | journal = Cancers | volume = 10 | issue = 11 | page = 396 | date = October 2018 | pmid = 30352966 | pmc = 6266412 | doi = 10.3390/cancers10110396 | doi-access = free }}</ref> Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.<ref>{{Cite journal| vauthors = Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, Kopeina GS, Lozinskaya NA|date=December 2021|title=Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors |journal=Medicinal Chemistry Research|language=en|volume=30|issue=12|pages=2216–2227|doi=10.1007/s00044-021-02802-w|s2cid=241788123 |issn=1054-2523}}</ref><ref>{{cite journal | vauthors = Bazanov DR, Pervushin NV, Savitskaya VY, Anikina LV, Proskurnina MV, Lozinskaya NA, Kopeina GS | title = 2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation | journal = Bioorganic & Medicinal Chemistry Letters | volume = 29 | issue = 16 | pages = 2364–2368 | date = August 2019 | pmid = 31196710 | doi = 10.1016/j.bmcl.2019.06.007 | s2cid = 189815065 }}</ref><ref>{{cite journal | vauthors = Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Savitskaya VY, Sosonyuk SE, Gracheva YA, Seliverstov MY, Lozinskaya NA, Kopeina GS | title = Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core | journal = Pharmaceuticals | volume = 15 | issue = 4 | pages = 444 | date = April 2022 | pmid = 35455441 | pmc = 9027661 | doi = 10.3390/ph15040444 | doi-access = free }}</ref> |
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==References== |
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{{Reflist}} |
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== References == |
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{{Organic-compound-stub}} |
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{{Reflist}} |
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