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
3D model (JSmol)
ChEMBL
UNII
  • 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
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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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] 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.[3] 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] Nutlin-3 has been shown to affect the production of p53 within minutes.[4]

The more potent of the two enantiomers, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion.[5] Several derivatives of nutlin, such as RG7112 and RG7388 (Idasanutlin) have been developed and progressed into human studies.[6] Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.[7][8][9]

References

  1. ^ Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. (February 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. S2CID 16132757.
  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". Annual Review of Pharmacology and Toxicology. 49: 223–241. doi:10.1146/annurev.pharmtox.48.113006.094723. PMC 2676449. PMID 18834305.
  3. ^ Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. (February 2006). "Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy". Proceedings of the National Academy of Sciences of the United States of America. 103 (6): 1888–1893. doi:10.1073/pnas.0507493103. PMC 1413632. PMID 16443686.
  4. ^ van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, et al. (May 2011). "Mechanism-specific signatures for small-molecule p53 activators". Cell Cycle. 10 (10). Landes Bioscience: 1590–1598. doi:10.4161/cc.10.10.15519. PMID 21490429.
  5. ^ Davis TA, Johnston JN (January 2011). "Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor". Chemical Science. 2 (6): 1076–1079. doi:10.1039/C1SC00061F. PMC 3375951. PMID 22708054.
  6. ^ Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, et al. (October 2018). "Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells". Cancers. 10 (11): 396. doi:10.3390/cancers10110396. PMC 6266412. PMID 30352966.
  7. ^ Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, et al. (December 2021). "Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors". Medicinal Chemistry Research. 30 (12): 2216–2227. doi:10.1007/s00044-021-02802-w. ISSN 1054-2523. S2CID 241788123.
  8. ^ Bazanov DR, Pervushin NV, Savitskaya VY, Anikina LV, Proskurnina MV, Lozinskaya NA, et al. (August 2019). "2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation". Bioorganic & Medicinal Chemistry Letters. 29 (16): 2364–2368. doi:10.1016/j.bmcl.2019.06.007. PMID 31196710. S2CID 189815065.
  9. ^ Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Savitskaya VY, et al. (April 2022). "Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core". Pharmaceuticals. 15 (4): 444. doi:10.3390/ph15040444. PMC 9027661. PMID 35455441.