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Investigational New Drugs

, Volume 27, Issue 2, pp 131–139 | Cite as

Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study

  • Ananda Kumar C. S.
  • S. B. Benaka Prasad
  • K. Vinaya
  • S. Chandrappa
  • N. R. Thimmegowda
  • S. R. Ranganatha
  • Sanjay Swarup
  • K. S. RangappaEmail author
PHASE I STUDIES

Summary

In the course of structure–activity relationship studies and to explore the antiproliferative effect associated with the hydantoin framework, diversely substituted several diazaspiro hydantoins were synthesized. Variation in the functional group at N-terminal of the hydantoin ring and coupling of different substituted aromatic acids in 4-aminocyclohexanone ring led to three sets of compounds. The antiproliferative effect of the compounds was evaluated in vitro using the MTT colorimetric method against one normal cell line (NDF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, some compounds exhibited interesting growth inhibitory effects against all four cell lines. From the SAR studies, it reveals that, the substitution at N-terminal in hydantoin ring plays key role in the antiproliferative activity.

Keywords

Diazaspiro hydantoins 4-amino cyclohexanone Antiproliferative activity Cell proliferation Carcinoma cell lines MTT assay 

Notes

Acknowledgements

The authors are grateful to UGC, Govt. of India for financial support to K.S.R. under the project UGC-SAP (Phase I) vide No. F. 540/10/2004-05 (SAP I).

References

  1. 1.
    Sawyers C (2004) Targeted cancer therapy. Nature 432:294–297 doi: 10.1038/nature03095 PubMedCrossRefGoogle Scholar
  2. 2.
    Li Q, Xu W (2005) Novel anticancer targets and drug discovery in post genomic age. Curr Med Chem Anticancer Agents 5:53–63 doi: 10.2174/1568011053352631 PubMedCrossRefGoogle Scholar
  3. 3.
    Mencher SK, Wang LG (2005) Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin Pharmacol 5:3 doi: 10.1186/1472-6904-5-3 PubMedCrossRefGoogle Scholar
  4. 4.
    Jimeno A, Hidalgo M (2006) Multitargeted therapy: can promiscuity be praised in an era of political correctness. Crit Rev Oncol Hematol 59:150–158 doi: 10.1016/j.critrevonc.2006.01.005 PubMedCrossRefGoogle Scholar
  5. 5.
    Karolacawojciechowska J, Kwiatkowski W, Kieckonono K (1995) Structural and electronic conditions for anticonvulsant activity of bicyclic hydantoin derivatives. Pharmazie 50:114–117Google Scholar
  6. 6.
    Brouillette WJ, Brown GB, Deloreg TM, Liang G (1990) Sodium channel binding and anticonvulsant activities of hydantoins containing conformationally constrained 5-phenyl substituents. J Pharm Sci 79:871–884 doi: 10.1002/jps.2600791005 PubMedCrossRefGoogle Scholar
  7. 7.
    Brouillette WJ, Jestkov VP, Brown ML, Akhtar MS (1994) Bicyclic hydantoins with a bridgehead nitrogen. Comparison of anticonvulsant activities with binding to the neuronal voltage-dependent sodium channel. J Med Chem 37:3289–3293 doi: 10.1021/jm00046a013 PubMedCrossRefGoogle Scholar
  8. 8.
    Carmi C, Cavazzoni A, Zuliani V, Lodola A, Bordi F, Plazzi PV et al (2006) 5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity. Bioorg Med Chem Lett 16:4021–4025 doi: 10.1016/j.bmcl.2006.05.010 PubMedCrossRefGoogle Scholar
  9. 9.
    Hah SS, Kim HM, Sumbad RA, Henderson PT (2005) Hydantoin derivative formation from oxidation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) and incorporation of 14C-labeled 8-oxodG into the DNA of human breast cancer cells. Bioorg Med Chem Lett 15:3627–3631 doi: 10.1016/j.bmcl.2005.05.113 PubMedCrossRefGoogle Scholar
  10. 10.
    Chinnappa J, Thenmozhiyal, Wong PT, Chui WK (2004) Anticonvulsant activity of Phenylmethylenehydantoins: a structure–activity relationship study. J Med Chem 47:1527–1535 doi: 10.1021/jm030450c CrossRefGoogle Scholar
  11. 11.
    Ahmed KI (1998) Synthesis of Arylidenehydrazano- and Glycopyranosylhydrazino sulfonyl benzylidenediones as potential antiviral and antitumoral agents. Carbohydr Res 306(4):567–573 doi: 10.1016/S0008-6215(98)00024-X CrossRefGoogle Scholar
  12. 12.
    Rodgers TR, LaMontagne MP, Markovac A, Ash AB (1977) Hydantoins as antitumor agents. J Med Chem 20:591–594 doi: 10.1021/jm00214a031 PubMedCrossRefGoogle Scholar
  13. 13.
    Comber RN, Reynolds RC, Friedrich JD, Manguikian RA, Buckheit RW, Truss JJW et al (1992) 5,5-Disubstituted hydantoins: syntheses and anti-HIV Activity. J Med Chem 35:3567–3572 doi: 10.1021/jm00097a014 PubMedCrossRefGoogle Scholar
  14. 14.
    Somsak L, Kovacs L, Toth M, Osz E, Szilagyi L, Gyorgydeak Z et al (2001) Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of d-gluco- and d-xylopyranosylidene-spiro-(thio)hydantoins and N-(d-glucopyranosyl) amides. J Med Chem 44:2843–2848 doi: 10.1021/jm010892t PubMedCrossRefGoogle Scholar
  15. 15.
    Bazil CW, Pedley TA (1998) Advances in the medical treatment of epilepsy. Annu Rev Med 49:135–162 doi: 10.1146/annurev.med.49.1.135 PubMedCrossRefGoogle Scholar
  16. 16.
    Luer MS (1998) Fosphenytoin. Neurol Res 20:178–182PubMedGoogle Scholar
  17. 17.
    Matsukura M, Daiku Y, Ueda K, Tanaka S, Igarashi T, Minami N (1992) Synthesis and antiarrhythmic activity of 2,2-dialkyl-1'-(N-substituted aminoalkyl)-spiro-(chroman-4,4'-imidazolidine)-2',5'-diones. Chem Pharm Bull (Tokyo) 40:1823–1827Google Scholar
  18. 18.
    Knabe J, Baldauf J, Ahlhelm A (1997) Racemates and enantiomers of basic, substituted 5-phenylhydantoins, synthesis and anti-arrhythmic action. Pharmazie 52:912–919PubMedGoogle Scholar
  19. 19.
    Menendez JC, Diaz MP, Bellver C, Sollhuber MM (1992) Synthesis, anticonvulsant and antihypertensive activity of diastereomeric 9,10-dimethoxy-1,3,4,6,7,11b-hexahydrospiro-[benzo[a]quinolizin-2,4-imidazolidine]-2',5'-diones. Eur J Med Chem 27:61–66 doi: 10.1016/0223-5234(92)90062-6 CrossRefGoogle Scholar
  20. 20.
    Moloney GP, Robertson AD, Martin GR, MacLennan S, Mathews N, Dosworth S et al (1997) A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT1B/1D receptor antagonists. J Med Chem 40:2347–2362 doi: 10.1021/jm9605849 PubMedCrossRefGoogle Scholar
  21. 21.
    Moloney GP, Martin GR, Mathews N, Milne A, Hobbs H, Dosworth S (1999) Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT(1B)-like receptor. J Med Chem 42:2504–2526 doi: 10.1021/jm9706325 PubMedCrossRefGoogle Scholar
  22. 22.
    Jansen M, Potschka H, Brandt C, Loscher W, Dannhardt G (2003) Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. J Med Chem 46:64–73 doi: 10.1021/jm020955n PubMedCrossRefGoogle Scholar
  23. 23.
    Last-Barney K, Davidson W, Cardozo M, Frye LL, Grygon CA, Hopkins JL et al (2001) Binding site elucidation of hydantoin-based antagonists of LFA-1 using multidisciplinary technologies: evidence for the allosteric inhibition of a protein–protein interaction. J Am Chem Soc 123:5643–5650 doi: 10.1021/ja0104249 PubMedCrossRefGoogle Scholar
  24. 24.
    Chandrappa S, Benaka Prasad SB, Vinaya K, Ananda Kumar CS, Thimmegowda NR, Rangappa KS (2008) Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones. Invest New Drugs doi: 10.1007/s10637-008-9130-7
  25. 25.
    Ananda Kumar CS, Nanjunda Swamy S, Thimmegowda NR, Benaka Prasad SB, Yip GW, Rangappa KS (2007) Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation. Med Chem Res 16:179–187 doi: 10.1007/s00044-007-9022-y CrossRefGoogle Scholar
  26. 26.
    Anil Kumar C, Nanjunda Swamy S, Gaonkar SL, Basappa, Bharathi PS, Rangappa KS (2007) N-substituted-2-butyl-5-chloro-3H-imidazole-4-carbalderhyde derivatives as anti-tumor agents against ehrilch ascites tumor cells in vivo. Med Chem 3:269–276 doi: 10.2174/157340607780620699 PubMedCrossRefGoogle Scholar
  27. 27.
    Anil Kumar C, Jayarama S, Basappa, Bharathi PS, Rangappa KS (2007) Pro-apoptotic activity of imidazole derivatives mediated by up-regulation of Bax and activation of CAD in Ehrlich ascites tumor cells. Invest New Drugs 25:343–350 doi: 10.1007/s10637-006-9033-4 PubMedCrossRefGoogle Scholar
  28. 28.
    Bucherer HT, Steiner W (1934) Syntheses of hydantoins. I. Reactions of a-hydroxy and a-amino nitriles. J Prakt Chem 140:291–316Google Scholar
  29. 29.
    Ware E (1950) The chemistry of hydantoins. Chem Rev 46:403–470 doi: 10.1021/cr60145a001 CrossRefGoogle Scholar
  30. 30.
    Wysong CL, Yokum TS, Morales GA, Gundry Rl, McLaughlin ML, Hammer RP (1996) 4-Aminopiperidine-4-carboxylic acid: cyclic A. a, a-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 61:7650–7651PubMedCrossRefGoogle Scholar
  31. 31.
    Yokum TS, Bursavich MG, Sarina A, Paul P, Hall DA, McLaughlin ML (1997) Synthesis of a series of polar, orthoginally protected, a, a-disubstituted amino acids. Tetrahedron Lett 38:4013–4016 doi: 10.1016/S0040-4039(97)00822-8 CrossRefGoogle Scholar
  32. 32.
    Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH et al (1988) Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48:4827–4833PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ananda Kumar C. S.
    • 1
  • S. B. Benaka Prasad
    • 1
  • K. Vinaya
    • 1
  • S. Chandrappa
    • 1
  • N. R. Thimmegowda
    • 1
  • S. R. Ranganatha
    • 1
  • Sanjay Swarup
    • 2
  • K. S. Rangappa
    • 1
    Email author
  1. 1.Department of Studies in ChemistryUniversity of MysoreMysoreIndia
  2. 2.Department of Biological SciencesNational University of SingaporeSingaporeSingapore

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