Topics in Current Chemistry

, 375:3 | Cite as

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Review

Abstract

As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53–MDM2 protein–protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53–MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure–activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer.

Graphical Abstract

Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53–MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure–activity relationship.

Keywords

p53–MDM2 interaction Small molecule inhibitors Spiro-oxindoles Anticancer 

Notes

Acknowledgements

AKG acknowledges the Department of Science and Technology (DST, New Delhi) for financial support under the Women Scientist Project Scheme (WOS-A).

Compliance with ethical standards

Conflict of interest

Alpana K. Gupta, Mausumi Bharadwaj, Anoop Kumar, and Ravi Mehrotra declare that they have no conflict of interest.

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) CA Cancer J Clin 65:87–108CrossRefGoogle Scholar
  2. 2.
    WHO (2014) World cancer report, Chap 1.1. WHO, GenevaGoogle Scholar
  3. 3.
    Chabner BA, Roberts TG Jr (2005) Nat Rev Cancer 5:65–72CrossRefGoogle Scholar
  4. 4.
    Lind MJ (2011) Principles of cytotoxic chemotherapy. Medicine 39(12):711–716CrossRefGoogle Scholar
  5. 5.
    Rheingold SR, Neugut AI, Meadows AT (2003) Secondary cancers: incidence, risk factors, and management. Chapter 159. In: Kufe DW, Pollock RE, Weichselbaum RR et al (eds) Holland-Frei cancer medicine, 6th edn. BC Decker, HamiltonGoogle Scholar
  6. 6.
    Schreiber SL (2003) Chem Eng News 81:51–61CrossRefGoogle Scholar
  7. 7.
    Bae YH, Mrsny RJ, Park K (2013) Cancer targeted drug delivery: an elusive dream. Springer, BerlinCrossRefGoogle Scholar
  8. 8.
    Aggarwal S (2010) Nat Rev Drug Discov 9:427–428CrossRefGoogle Scholar
  9. 9.
    Chessum N, Jones K, Pasqua E, Tucker M (2015) Prog Med Chem 54:1–63CrossRefGoogle Scholar
  10. 10.
    Stratton MR (2011) Science 331:1553–1558CrossRefGoogle Scholar
  11. 11.
    Collins I, Workman P (2006) Nat Chem Biol 2:689–700CrossRefGoogle Scholar
  12. 12.
    Kummar S, Murgo AJ, Tomasze JE, Doroshow JH (2014) Therapeutic targeting of cancer cells: era of molecularly targeted agents. Elsevier Churchill Livingstone, PhiladelphiaGoogle Scholar
  13. 13.
    Gerber DE (2008) Am Fam Physician 77:311–319Google Scholar
  14. 14.
    Lacroix M (2014) Targeted therapies in cancer. Nova Sciences, Hauppauge. ISBN 978-1-63321-687-7Google Scholar
  15. 15.
    Tanner JE (2005) Cancer Metastasis Rev 24:585–598CrossRefGoogle Scholar
  16. 16.
    Avendano C, Menendez JC (2015) Medicinal chemistry of anticancer drugs, 2nd edn. Elsevier, AmsterdamGoogle Scholar
  17. 17.
    Zhao Y, Bernard D, Wang S (2013) BioDiscovery 8(4):1–15Google Scholar
  18. 18.
    Dickens MP, Fitzgerald R, Fischer PM (2010) Semin Cancer Biol 20:10–18CrossRefGoogle Scholar
  19. 19.
    Zhao Y, Aguilar A, Bernard D, Wang S (2015) J Med Chem 58:1038–1052CrossRefGoogle Scholar
  20. 20.
    Vanneman M, Dranoff G (2012) Nat Rev Cancer 12:237–251CrossRefGoogle Scholar
  21. 21.
    Masters GA, Krilov L, Bailey HH, Brose MS, Burstein H, Diller LR, Dizon DS, Fine HA, Kalemkerian GP, Moasser M, Neuss MN, O’Day SJ, Odenike O, Ryan CJ, Schilsky RL, Schwartz GK, Venook AP, Wong SL, Patel JD (2015) J Clin Oncol 33:786–809CrossRefGoogle Scholar
  22. 22.
    Abramson R (2015) Overview of targeted therapies for cancer. My Cancer Genome. https://www.mycancergenome.org/content/molecular-medicine/overview-of-targeted-therapies-for-cancer/. Accessed 1 Jan 2016
  23. 23.
    Mullard A (2015) Nat Rev Drug Discov 14:77–81CrossRefGoogle Scholar
  24. 24.
    Wang S, Zhao Y, Bernard D, Aguilar A, Kumar S (2012) Top Med Chem 8:57–80CrossRefGoogle Scholar
  25. 25.
    Lane DP, Cheok CF, Lain S (2010) Cold Spring Harb Perspect Biol 2:a001222Google Scholar
  26. 26.
    Vogelstein B, Lane D, Levine AJ (2000) Nature 408:307–310CrossRefGoogle Scholar
  27. 27.
    Moll UM, Petrenko O (2003) Mol Cancer Res 1:1001–1008Google Scholar
  28. 28.
    Fu T, Min H, Xu Y, Chen J, Li G (2012) Int J Mol Sci 13:9709–9740CrossRefGoogle Scholar
  29. 29.
    Vu BT, Vassilev L (2011) Curr Top Microbiol Immunol 348:151–172Google Scholar
  30. 30.
    Picksley SM, Lane DP (1993) BioEssays 15:689–690CrossRefGoogle Scholar
  31. 31.
    Wade M, Wang YV, Wahl GM (2010) Trends Cell Biol 20:299–309CrossRefGoogle Scholar
  32. 32.
    Momand J, Wu HH, Dasgupta G (2000) Gene 242:15–29CrossRefGoogle Scholar
  33. 33.
    Hainaut P, Hollstein M (2000) Adv Cancer Res 77:81–137CrossRefGoogle Scholar
  34. 34.
    Vousden KH, Lu X (2002) Nat Rev Cancer 2:594–604CrossRefGoogle Scholar
  35. 35.
    Riedinger C, McDonnell JM (2009) Future Med Chem 1:1075–1094CrossRefGoogle Scholar
  36. 36.
    Shangary S, Wang S (2009) Annu Rev Pharmacol Toxicol 49:223–241CrossRefGoogle Scholar
  37. 37.
    Chene P (2003) Nat Rev Cancer 3:102–109CrossRefGoogle Scholar
  38. 38.
    Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S (2008) Proc Natl Acad Sci USA 105:3933–3938CrossRefGoogle Scholar
  39. 39.
    Zhang R, Wang H, Agrawal S (2005) Curr Cancer Drug Targets 5:43–49CrossRefGoogle Scholar
  40. 40.
    Herman AG, Hayano M, Poyurovsky MV, Shimada K, Skouta R, Prives C, Stockwell BR (2011) Cancer Discov 1:312–325CrossRefGoogle Scholar
  41. 41.
    Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, Van Pelt CS, Lozano G (2008) Genes Dev 22:1337–1344CrossRefGoogle Scholar
  42. 42.
    Hoelder S, Clarke PA, Workman P (2012) Mol Oncol 6:155–176CrossRefGoogle Scholar
  43. 43.
    Azmi AS, Beck FW, Sarkar FH, Mohammad RM (2011) Curr Pharm Des 17:640–652CrossRefGoogle Scholar
  44. 44.
    Zheng T, Wang J, Song X, Meng X, Pan S, Jiang H, Liu L (2010) J Cancer Res Clin Oncol 136:1597–1604CrossRefGoogle Scholar
  45. 45.
    Wade M, Li YC, Wahl GM (2013) Nat Rev Cancer 13:83–96CrossRefGoogle Scholar
  46. 46.
    Millard M, Pathania D, Grande F, Xu S, Neamati N (2011) Curr Pharm Des 17:536–559CrossRefGoogle Scholar
  47. 47.
    Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Science 274:948–953CrossRefGoogle Scholar
  48. 48.
    Vazquez A, Bond EE, Levine AJ, Bond GL (2008) Nat Rev Drug Discov 7:979–987CrossRefGoogle Scholar
  49. 49.
    Pujals A, Favre L, Gaulard P, Wiels J (2015) Activation of wild-type p53 by MDM2 inhibitors: a new strategy for lymphoma treatment. Blood Lymphat Cancer 5:93–100Google Scholar
  50. 50.
    Khoo KH, Verma CS, Lane DP (2014) Nat Rev Drug Discov 13:217–236CrossRefGoogle Scholar
  51. 51.
    Wade M, Wahl GM (2009) Mol Cancer Res 7:1–11CrossRefGoogle Scholar
  52. 52.
    Qin JJ, Wang W, Voruganti S, Wang H, Zhang WD, Zhang R (2015) Oncotarget 6:2623–2640Google Scholar
  53. 53.
    Qin JJ, Nag S, Voruganti S, Wang W, Zhang R (2012) Curr Med Chem 19:5705–5725CrossRefGoogle Scholar
  54. 54.
    Bottger V, Bottger A, Howard SF, Picksley SM, Chene P, Garcia-Echeverria C, Hochkeppel HK, Lane DP (1996) Oncogene 13:2141–2147Google Scholar
  55. 55.
    Kritzer JA, Lear JD, Hodsdon ME, Schepartz A (2004) J Am Chem Soc 126:9468–9469CrossRefGoogle Scholar
  56. 56.
    Zhang Q, Zeng SX, Lu H (2014) Subcell Biochem 85:281–319CrossRefGoogle Scholar
  57. 57.
    Aeluri M, Chamakuri S, Dasari B, Guduru SK, Jimmidi R, Jogula S, Arya P (2014) Chem Rev 114:4640–4649CrossRefGoogle Scholar
  58. 58.
    Carry JC, Garcia-Echeverria C (2013) Bioorg Med Chem Lett 23:2480–2485CrossRefGoogle Scholar
  59. 59.
    Vassilev Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) Science 303:844–848CrossRefGoogle Scholar
  60. 60.
    Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT (2013) Cancer Res 73:2587–2597CrossRefGoogle Scholar
  61. 61.
    Ray-Coquard I, Blay JY, Italiano A, Le CA, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL, Bui BN (2012) Lancet Oncol 13:1133–1140CrossRefGoogle Scholar
  62. 62.
    Rew Y, Sun D, De Gonzalez-Lopez TF, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Deignan J, Fox BM, Gustin D, Huang X, Jiang M, Jiao X, Jin L, Kayser F, Kopecky DJ, Li Y, Lo MC, Long AM, Michelsen K, Oliner JD, Osgood T, Ragains M, Saiki AY, Schneider S, Toteva M, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Medina JC, Olson SH (2012) J Med Chem 55:4936CrossRefGoogle Scholar
  63. 63.
    Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D, Deignan J, Duquette J, Eksterowicz J, Fisher B, Fox BM, Fu J, Gonzalez AZ, De Gonzalez-Lopez TF, Houze JB, Huang X, Jiang M, Jin L, Kayser F, Liu JJ, Lo MC, Long AM, Lucas B, McGee LR, McIntosh J, Mihalic J, Oliner JD, Osgood T, Peterson ML, Roveto P, Saiki AY, Shaffer P, Toteva M, Wang Y, Wang YC, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Yu M, Zhao X, Zhou J, Zhu J, Olson SH, Medina JC (2014) J Med Chem 57:1454–1472CrossRefGoogle Scholar
  64. 64.
    Gonzalez AZ, Li Z, Beck HP, Canon J, Chen A, Chow D, Duquette J, Eksterowicz J, Fox BM, Fu J, Huang X, Houze J, Jin L, Li Y, Ling Y, Lo MC, Long AM, McGee LR, McIntosh J, Oliner JD, Osgood T, Rew Y, Saiki AY, Shaffer P, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Olson SH, Sun D, Medina JC (2014) J Med Chem 57:2963–2988CrossRefGoogle Scholar
  65. 65.
    Canon J, Osgood T, Olson SH, Saiki AY, Robertson R, Yu D, Eksterowicz J, Ye Q, Jin L, Chen A, Zhou J, Cordover D, Kaufman S, Kendall R, Oliner JD, Coxon A, Radinsky R (2015) Mol Cancer Ther 14:649–658CrossRefGoogle Scholar
  66. 66.
    Raboisson P, Marugan JJ, Schubert C, Koblish HK, Lu T, Zhao S, Player MR, Maroney AC, Reed RL, Huebert ND, Lattanze J, Parks DJ, Cummings MD (2005) Bioorg Med Chem Lett 15:1857–1861CrossRefGoogle Scholar
  67. 67.
    Marugan JJ, Leonard K, Raboisson P, Gushue JM, Calvo R, Koblish HK, Lattanze J, Zhao S, Cummings MD, Player MR, Schubert C, Maroney AC, Lu T (2006) Bioorg Med Chem Lett 16:3115–3120CrossRefGoogle Scholar
  68. 68.
    Allen JG, Bourbeau MP, Wohlhieter GE, Bartberger MD, Michelsen K, Hungate R, Gadwood RC, Gaston RD, Evans B, Mann LW, Matison ME, Schneider S, Huang X, Yu D, Andrews PS, Reichelt A, Long AM, Yakowec P, Yang EY, Lee TA, Oliner JD (2009) J Med Chem 52:7044–7053CrossRefGoogle Scholar
  69. 69.
    Beck HP, DeGraffenreid M, Fox B, Allen JG, Rew Y, Schneider S, Saiki AY, Yu D, Oliner JD, Salyers K, Ye Q, Olson S (2011) Bioorg Med Chem Lett 21:2752–2755CrossRefGoogle Scholar
  70. 70.
    Yin H, Lee GI, Park HS, Payne GA, Rodriguez JM, Sebti SM, Hamilton AD (2005) Angew Chem Int Ed Engl 44:2704–2707CrossRefGoogle Scholar
  71. 71.
    Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HM, Lunec J (2006) J Med Chem 49:6209–6221CrossRefGoogle Scholar
  72. 72.
    Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B (2013) J Med Chem 56:5979–5983CrossRefGoogle Scholar
  73. 73.
    Ma Y, Lahue BR, Shipps GW Jr, Brookes J, Wang Y (2014) Bioorg Med Chem Lett 24:1026–1030CrossRefGoogle Scholar
  74. 74.
    Zak K, Pecak A, Rys B, Wladyka B, Domling A, Weber L, Holak TA, Dubin G (2013) Expert Opin Ther Pat 23:425–448CrossRefGoogle Scholar
  75. 75.
    Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding Y, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang S (2005) J Am Chem Soc 127:10130–10131CrossRefGoogle Scholar
  76. 76.
    Chen L, Han X, Yang S, Zhang Z (2012) 3,3′-Spiroindolinone derivatives and their use for cancer. Patent No. EP2421866A1Google Scholar
  77. 77.
    Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L (2014) Cancer Res 74:5855–5865CrossRefGoogle Scholar
  78. 78.
    Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K, Roller PP, Wang S (2006) J Med Chem 49:3432–3435CrossRefGoogle Scholar
  79. 79.
    Yu B, Yu DQ, Liu HM (2015) Eur J Med Chem 97:673–698CrossRefGoogle Scholar
  80. 80.
    Weber L (2010) Expert Opin Ther Pat 20:179–191CrossRefGoogle Scholar
  81. 81.
    Kamal A, Mohammed AA, Shaik TB (2012) Expert Opin Ther Pat 22:95–105CrossRefGoogle Scholar
  82. 82.
    Czarna A, Popowicz GM, Pecak A, Wolf S, Dubin G, Holak TA (2009) Cell Cycle 8:1176–1184CrossRefGoogle Scholar
  83. 83.
    Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J (2006) J Biol Chem 281:33030–33035CrossRefGoogle Scholar
  84. 84.
    Ding K, Wang G, Deschamps JR, Parrish DA, Wang S (2005) Tetrahedron Lett 46:5949–5951CrossRefGoogle Scholar
  85. 85.
    Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Proteins 52:609–623CrossRefGoogle Scholar
  86. 86.
    Wang S, Zhao Y, Sun W, Kumar S, Leopold L, Debussche L, Barriere C, Carry J-C, Amaning K (2014) Spiro-oxindole MDM2 antagonists. US 14/170,101 (US20140148494A1)Google Scholar
  87. 87.
    Shangary S, Ding K, Qiu S, Nikolovska-Coleska Z, Bauer JA, Liu M, Wang G, Lu Y, McEachern D, Bernard D, Bradford CR, Carey TE, Wang S (2008) Mol Cancer Ther 7:1533–1542CrossRefGoogle Scholar
  88. 88.
    Yu S, Qin D, Shangary S, Chen J, Wang G, Ding K, McEachern D, Qiu S, Nikolovska-Coleska Z, Miller R, Kang S, Yang D, Wang S (2009) J Med Chem 52:7970–7973CrossRefGoogle Scholar
  89. 89.
    Huang W, Cai L, Chen C, Xie X, Zhao Q, Zhao X, Zhou HY, Han B, Peng C (2016) J Biomol Struct Dyn 34:341–351CrossRefGoogle Scholar
  90. 90.
    Aguilar A, Sun W, Liu L, Lu J, McEachern D, Bernard D, Deschamps JR, Wang S (2014) J Med Chem 57:10486–10498CrossRefGoogle Scholar
  91. 91.
    Ball-Jones NR, Badillo JJ, Franz AK (2012) Org Biomol Chem 10:5165–5181CrossRefGoogle Scholar
  92. 92.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727–748CrossRefGoogle Scholar
  93. 93.
    Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA (2010) Cell Cycle 9:1104–1111CrossRefGoogle Scholar
  94. 94.
    Khan A, Lu H (2008) Cancer Biol Ther 7:853–855CrossRefGoogle Scholar
  95. 95.
    Sun SH, Zheng M, Ding K, Wang S, Sun Y (2008) Cancer Biol Ther 7:845–852CrossRefGoogle Scholar
  96. 96.
    Azmi AS, Aboukameel A, Banerjee S, Wang Z, Mohammad M, Wu J, Wang S, Yang D, Philip PA, Sarkar FH, Mohammad RM (2010) Eur J Cancer 46:1122–1131CrossRefGoogle Scholar
  97. 97.
    Azmi AS, Philip PA, Aboukameel A, Wang Z, Banerjee S, Zafar SF, Goustin AS, Almhanna K, Yang D, Sarkar FH, Mohammad RM (2010) Curr Cancer Drug Targets 10:319–331CrossRefGoogle Scholar
  98. 98.
    Mohammad RM, Wu J, Azmi AS, Aboukameel A, Sosin A, Wu S, Yang D, Wang S, Al-Katib AM (2009) Mol Cancer 8:115CrossRefGoogle Scholar
  99. 99.
    Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T, Zou P, Sun D, Wang S (2013) J Med Chem 56:5553–5561CrossRefGoogle Scholar
  100. 100.
    Wang S, Sun W, Yu S et al (2011) Highly potent and optimized small-molecule inhibitors of MDM2 achieve complete tumor regression in animal models of solid tumors and leukemia. Abstract LB-204. AACR 102nd annual meeting, Orlando, FLGoogle Scholar
  101. 101.
    Bill KL, Garnett J, Meaux I, Ma X, Creighton CJ, Bolshakov S, Barriere C, Debussche L, Lazar AJ, Prudner BC, Casadei L, Braggio D, Lopez G, Zewdu A, Bid H, Lev D, Pollock RE (2016) Clin Cancer Res 22:1150–1160CrossRefGoogle Scholar
  102. 102.
    Chen L, Ding Q, Liu J, Yang S, Zhang Z, Hoffmann-La RIU (2009) Spiroindolinone derivatives. US7495007 B2Google Scholar
  103. 103.
    Chen L, Han X, Yang S, Zhang Z (2010) Preparation of 3,3′-spiroindolinones for treatment of cancer. WO 2010121995 A1Google Scholar
  104. 104.
    Chen L, Han X, He Y, Yang S, Zhang Z. Hoffman-La Roche Inc, USA (2009) Spiroindolinone derivatives as interaction inhibitors between p53 and MDM2 proteins and their preparation, pharmaceutical compositions and use in the treatment of cancer. US 20090163512 A1Google Scholar
  105. 105.
    Ding Q, Liu JJ, Zhang Z. Zhang Z, Hoffmann La Roche, Switzerland (2007) Spiroindolinone derivatives. WO 2007104714 A1Google Scholar
  106. 106.
    Chen L, Ding Q, Liu JJ, Yang S, Zhang Z (2007) Preparation of spiroindolinone derivatives as antitumor agents. US 20070213341 A1Google Scholar
  107. 107.
    Ding Q, Jiang N, Yang S, Zhang J, Zhang Z (2009) Spiroindolinone derivatives. US 20090156610 A1Google Scholar
  108. 108.
    Liu JJ, Zhang Z. (2009) Spiroindolinone derivatives. US 7638548 B2Google Scholar
  109. 109.
    Chen L, Han X, Yang S, Zhang Z (2010) Spiroindolinone pyridine derivatives as inhibitors of MDM2–p53 protein interaction useful as potent and selective anticancer agents and preparation thereof. US 20100204257Google Scholar
  110. 110.
    Zhang J, Zhang Z Spiroindolinone pyridine derivatives as inhibitors of MDM2–p53 protein interaction useful as potent and selective anticancer agents and preparation thereof. US 20100210674Google Scholar
  111. 111.
    Liu J-J, Zhang Z, Hoffmann-La Roche (2008) Preparation of spiroindole pyridotriazinediones as anticancer drugs. WO 2008141975Google Scholar
  112. 112.
    Bertamino A, Soprano M, Musella S, Rusciano MR, Sala M, Vernieri E, Di Sarno V, Limatola A, Carotenuto A, Cosconati S, Grieco P, Novellino E, Illario M, Campiglia P, Gomez-Monterrey I (2013) J Med Chem 56:5407–5421CrossRefGoogle Scholar
  113. 113.
    Gomez-Monterrey I, Bertamino A, Porta A, Carotenuto A, Musella S, Aquino C, Granata I, Sala M, Brancaccio D, Picone D, Ercole C, Stiuso P, Campiglia P, Grieco P, Ianelli P, Maresca B, Novellino E (2010) J Med Chem 53:8319–8329CrossRefGoogle Scholar
  114. 114.
    Ribeiro CJ, Amaral JD, Rodrigues CM, Moreira R, Santos MM (2014) Bioorg Med Chem 22:577–584CrossRefGoogle Scholar
  115. 115.
    Liu J-J, Tilley JW, Zhang Z (2008) 3,3-Spiroindolinone derivatives. US 12/101182 US20080287421 A1Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Molecular Cytology, Department of Health Research (Govt. of India)National Institute of Cancer Prevention and Research (ICMR)NoidaIndia
  2. 2.Division of Molecular Genetics and BiochemistryNational Institute of Cancer Prevention and Research (ICMR)NoidaIndia

Personalised recommendations