Nutlin

Nutlin 3
Names
	IUPAC name (±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one
	Other names Nutlin
Identifiers
CAS Number	548472 ;
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL191334 ;
PubChem CID	16755649;
UNII	53IA0V845C ;
	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;
Properties
Chemical formula	C30H30Cl2N4O4
Molar mass	581.49 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

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;^[1] however, Nutlin-3 is the compound most commonly used in anti-cancer studies.^[2] 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. Nutlin-3 has been shown to affect the production of p53 within minutes.^[3]

The more potent of the two enantiomers, (−)-nutlin-3, can be synthesized in a highly enantioselective fashion.^[4] Several derivatives of nutlin, such as RG7112 and RG7388 have been developed and progressed into human studies.

References

↑ Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004). "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science. 303 (5659): 844–848. Bibcode:2004Sci...303..844V. doi:10.1126/science.1092472. PMID 14704432.
↑ Shangary S, Wang S (2008). "Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy". Annu Rev Pharmacol Toxicol. 49: 223–241. doi:10.1146/annurev.pharmtox.48.113006.094723. PMC 2676449. PMID 18834305.
↑ van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ & Laín S (15 May 2011). "Mechanism-specific signatures for small-molecule p53 activators". Cell Cycle. Landes Bioscience. 10 (10): 1590–8. doi:10.4161/cc.10.10.15519. PMID 21490429.
↑ Davis, Tyler A; Johnston, Jeffrey N (2011). "Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of (−)-Nutlin-3, a potent p53/MDM2 inhibitor". Chemical Science. 2 (6): 1076. doi:10.1039/C1SC00061F. PMC 3375951. PMID 22708054.

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[Nutlin-1] Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004). "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science. 303 (5659): 844–848. Bibcode:2004Sci...303..844V. doi:10.1126/science.1092472. PMID 14704432.

[annrev-2] Shangary S, Wang S (2008). "Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy". Annu Rev Pharmacol Toxicol. 49: 223–241. doi:10.1146/annurev.pharmtox.48.113006.094723. PMC 2676449. PMID 18834305.

[Leeuwen_et_al.-3] van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ & Laín S (15 May 2011). "Mechanism-specific signatures for small-molecule p53 activators". Cell Cycle. Landes Bioscience. 10 (10): 1590–8. doi:10.4161/cc.10.10.15519. PMID 21490429.

[4] Davis, Tyler A; Johnston, Jeffrey N (2011). "Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of (−)-Nutlin-3, a potent p53/MDM2 inhibitor". Chemical Science. 2 (6): 1076. doi:10.1039/C1SC00061F. PMC 3375951. PMID 22708054.