Nutlin: Difference between revisions

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

| Verifiedfields = changed

| Watchedfields = changed

| Name = Nutlin 3

| verifiedrevid = 433813167

| ImageFile = Nutlin 3 Structure.svg

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

|Section1={{Chembox Identifiers

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

| CASNo = 548472-68-0

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

| UNII = 53IA0V845C

| PubChem = 16755649

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

| ChEMBL = 191334

| 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

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

'''Nutlins''' are ''cis''-[[2-Imidazoline|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;<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 = 844–8 | date = February 2004 | pmid = 14704432 | doi = 10.1126/science.1092472 | bibcode = 2004Sci...303..844V | s2cid = 16132757 }}</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 = 223–41 | 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 = 1888–93 | 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 [[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.<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 = 1590–8 | date = May 2011 | pmid = 21490429 | doi = 10.4161/cc.10.10.15519 | publisher = Landes Bioscience | doi-access = free }}</ref>

The more potent of the two [[enantiomer]]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 ([[Idasanutlin]]) have been developed and progressed into human studies.<ref>{{cite journal | vauthors = Skalniak L | display-authors = etal | date = Nov 2018 | title = Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells | journal = Cancers (Basel) | volume = 10 | issue = 11| page = 396 | pmid = 30352966 | doi = 10.3390/cancers10110396 | pmc = 6266412 | doi-access = free }}</ref> Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.<ref>{{Cite journal|last1=Bazanov|first1=Daniil R.|last2=Pervushin|first2=Nikolay V.|last3=Savin|first3=Egor V.|last4=Tsymliakov|first4=Michael D.|last5=Maksutova|first5=Anita I.|last6=Sosonyuk|first6=Sergey E.|last7=Kopeina|first7=Gelina S.|last8=Lozinskaya|first8=Natalia A.|date=December 2021|title=Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors|url=https://link.springer.com/10.1007/s00044-021-02802-w|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|last1=Bazanov|first1=Daniil R.|last2=Pervushin|first2=Nikolay V.|last3=Savitskaya|first3=Victoria Yu.|last4=Anikina|first4=Lada V.|last5=Proskurnina|first5=Marina V.|last6=Lozinskaya|first6=Natalia A.|last7=Kopeina|first7=Gelina S.|date=August 2019|title=2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation|url=https://linkinghub.elsevier.com/retrieve/pii/S0960894X19303749|journal=Bioorganic & Medicinal Chemistry Letters|language=en|volume=29|issue=16|pages=2364–2368|doi=10.1016/j.bmcl.2019.06.007|pmid=31196710|s2cid=189815065 }}</ref><ref>{{Cite journal |last1=Bazanov |first1=Daniil R. |last2=Pervushin |first2=Nikolay V. |last3=Savin |first3=Egor V. |last4=Tsymliakov |first4=Michael D. |last5=Maksutova |first5=Anita I. |last6=Savitskaya |first6=Victoria Yu. |last7=Sosonyuk |first7=Sergey E. |last8=Gracheva |first8=Yulia A. |last9=Seliverstov |first9=Michael Yu. |last10=Lozinskaya |first10=Natalia A. |last11=Kopeina |first11=Gelina S. |date=2022-04-02 |title=Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core |journal=Pharmaceuticals |language=en |volume=15 |issue=4 |pages=444 |doi=10.3390/ph15040444 |pmid=35455441 |pmc=9027661 |issn=1424-8247|doi-access=free }}</ref>

== References ==

{{Reflist}}