nutlin

{{Use dmy dates|date=February 2022}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Chembox

| Verifiedfields = changed

| Watchedfields = changed

| Name = Nutlin 3

| verifiedrevid = 433813167

| ImageFile = Nutlin 3 Structure.svg

| ImageSize =

| IUPACName = (±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one

| OtherNames = Nutlin

|Section1={{Chembox Identifiers

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 548472-68-0

| ChEBI = 46742

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 191334

| ChemSpiderID = 187530

| DrugBank = DB17039

| EC_number = 637-233-8

| PubChem = 16755649

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 53IA0V845C

| StdInChI=1S/C30H30Cl2N4O4/c1-18(2)40-25-16-23(39-3)12-13-24(25)29-34-27(19-4-8-21(31)9-5-19)28(20-6-10-22(32)11-7-20)36(29)30(38)35-15-14-33-26(37)17-35/h4-13,16,18,27-28H,14-15,17H2,1-3H3,(H,33,37)/t27-,28+/m1/s1

| StdInChIKey = BDUHCSBCVGXTJM-IZLXSDGUSA-N

| 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

}}

|Section2={{Chembox Properties

| C=30|H=30|Cl=2|N=4|O=4

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|Section3={{Chembox Hazards

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Nutlins are cis-imidazoline analogs which inhibit the interaction between mdm2 and tumor suppressor p53, 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;{{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 }} however, Nutlin-3 is the compound most commonly used in anti-cancer studies.{{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 }} 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.{{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 }} Inhibiting the interaction between mdm2 and p53 stabilizes p53, and is thought to selectively induce a growth-inhibiting state called senescence 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.{{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 }}

The more potent of the two enantiomers, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion.{{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 }} Several derivatives of nutlin, such as RG7112 and RG7388 (Idasanutlin) have been developed and progressed into human studies.{{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 }} Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.{{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}}{{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 }}{{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 }}