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

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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.

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References

  1. Sawyers C (2004) Targeted cancer therapy. Nature 432:294–297 doi:10.1038/nature03095

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  5. Karolacawojciechowska J, Kwiatkowski W, Kieckonono K (1995) Structural and electronic conditions for anticonvulsant activity of bicyclic hydantoin derivatives. Pharmazie 50:114–117

    Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  Google Scholar 

  12. Rodgers TR, LaMontagne MP, Markovac A, Ash AB (1977) Hydantoins as antitumor agents. J Med Chem 20:591–594 doi:10.1021/jm00214a031

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  16. Luer MS (1998) Fosphenytoin. Neurol Res 20:178–182

    PubMed  CAS  Google Scholar 

  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) 40:1823–1827

    CAS  Google Scholar 

  18. Knabe J, Baldauf J, Ahlhelm A (1997) Racemates and enantiomers of basic, substituted 5-phenylhydantoins, synthesis and anti-arrhythmic action. Pharmazie 52:912–919

    PubMed  CAS  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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. 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

    Article  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  28. Bucherer HT, Steiner W (1934) Syntheses of hydantoins. I. Reactions of a-hydroxy and a-amino nitriles. J Prakt Chem 140:291–316

    CAS  Google Scholar 

  29. Ware E (1950) The chemistry of hydantoins. Chem Rev 46:403–470 doi:10.1021/cr60145a001

    Article  CAS  Google Scholar 

  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 61:7650–7651

    Article  PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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 48:4827–4833

    PubMed  CAS  Google Scholar 

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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).

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Authors and Affiliations

  1. Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, India

    Ananda Kumar C. S., S. B. Benaka Prasad, K. Vinaya, S. Chandrappa, N. R. Thimmegowda, S. R. Ranganatha & K. S. Rangappa

  2. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Sanjay Swarup

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  1. Ananda Kumar C. S.
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Correspondence to K. S. Rangappa.

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C. S., A.K., Prasad, S.B.B., Vinaya, K. et al. Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study. Invest New Drugs 27, 131–139 (2009). https://doi.org/10.1007/s10637-008-9150-3

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