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Synthesis, characterization and in vitro anti-tumor activities of novel 9-ethyl-9H-purine derivatives

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Summary

Newer series of 9-ethyl-9H-purine derivatives (EPD) were synthesized and screened for their efficacy in inhibiting the proliferation of various tumor cells in vitro. We evaluated the effects of EPD against HeLa, SiHa, CaSki (human cervical cancer cells), LM8, LM8G7 (murine osteosarcoma cells), OVSAHO and SKOV-3 (human ovarian cancer cells). The chemical structures of the EPD were confirmed by 1H NMR and LCMS analyses. The inhibitory effects of EPD were studied by using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and TetraColor One reagents. Furthermore, SAR studies revealed that the presence of trifluoromethoxy and trifluromethyl group in 4b and 4g, respectively are responsible for the significant activity of the EPD against cervical cancer cells and the presence of isopropoxy group in 4f has influence in inhibiting the proliferation of osteosarcoma and ovarian cancer cell types.

Scheme for the synthesis of 9-ethyl-9H-purine

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References

  1. Goff BA, Mandel L, Muntz HG, Melancon CH (2000) Ovarian carcinoma diagnosis. Cancer 89:2068–2075

    Article  CAS  PubMed  Google Scholar 

  2. Hietanen S, Lain S, Krausz E, Blattner C, Lane DP (2000) Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci 97:8501–8506

    Article  CAS  PubMed  Google Scholar 

  3. Butz K, Denk C, Ullmann A, Scheffner M, Hoppe-Seyler F (2000) Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc Natl Acad Sci 97:6693–6697

    Article  CAS  PubMed  Google Scholar 

  4. Thanh U, Barbie David A, Barbie DT, MacLaughlin SM, Donahoe PK (2003) Mullerian inhibiting substance inhibits cervical cancer cell growth via a pathway involving p130 and p107. Proc Natl Acad Sci 100:15601–15606

    Article  Google Scholar 

  5. Smith KO, Galloway KS, Kennell WL, Ogilvie KK, Radotus BK (1982) A new nucleoside analog, 9-[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 22:55

    CAS  PubMed  Google Scholar 

  6. Skiper HE, Montgomery JA, Thomson JR, Schabel FM (1959) Structure-activity relationships and cross-resistance observed on evaluation of a series of purine analogs against experimental neoplasms. Cancer Res 19:287–308

    Google Scholar 

  7. Kidder GW, Dewey VC, Parks RE Jr, Woodside GL (1951) Further evidence on the mode of action of 8-azaguanine (guanazolo) in tumor inhibition. Cancer Res 11(3):204–211

    CAS  PubMed  Google Scholar 

  8. Baker BR, Wood WF (1967) Irreversible enzyme inhibitors. CII. On the mode of phenyl binding of 9-phenylguanine to guanine deaminase and xanthine oxidase. J Med Chem 10(6):1101–1105

    Article  CAS  PubMed  Google Scholar 

  9. Daly JW, Padgett WL, Shamim MT (1986) Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors. J Med Chem 29:1305–1308

    Article  CAS  PubMed  Google Scholar 

  10. Chen LS, Sheppard TL (2004) Chain termination and inhibition of Saccharomyces cerevisiae poly(A) polymerase by C-8-modified ATP analogs. J Biol Chem 279:40405–40411

    Article  CAS  PubMed  Google Scholar 

  11. Honma Y, Niitsu N (2000) Vidarabine and 2-deoxycoformycin as antileukemic agents monocytic leukemia. Leuk Lymphoma 39:57–66

    CAS  PubMed  Google Scholar 

  12. Levenson R, Kernen J, Housman D (1979) Synchronization of MEL cell commitment with cordycepin. Cell 18:1073–1078

    Article  CAS  PubMed  Google Scholar 

  13. Niitsu N, Umeda M, Honma Y (2000) Myeloid and monocytoid leukemia cells have different sensitivity to differentiation-inducing activity of deoxyadenosine analogs. Leuk Res 24:1–9

    Article  CAS  PubMed  Google Scholar 

  14. Koc Y, Urbano AG, Sweeney EB, McCaVrey R (1996) Induction of apoptosis by cordycepin in ADA-inhibited TdT-positive leukemia cells. Leukemia 10:1019–1024

    CAS  PubMed  Google Scholar 

  15. Niitsu N, Yamaguchi Y, Umeda M, Honma Y (1998) Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2’-deoxycoformycin and 2’- deoxy adenosine : association with dATP-dependent activation of caspase-3. Blood 92:3368–3375

    CAS  PubMed  Google Scholar 

  16. Wu JY, Zhang QX, Leung PH (2007) Inhibitory effects of ethyl acetate extract of Cordyceps sinensis mycelium on various cancer cells in culture and B16 in C57BL/6 mice. Phytomedicine 14:43–49

    Article  PubMed  Google Scholar 

  17. Wu WC, Hsiao JR, Lian YY, Lin CY, Huang BM (2007) The apoptotic effect of cordycepin on human OEC-M1 oral cancer cell line. Cancer Chemother Pharmacol 60:103–111

    Article  CAS  PubMed  Google Scholar 

  18. Gray NS, Wodicka L, Thunnissen AM, Nornam TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, Leclerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG (1998) Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281(5376):533–538

    Article  CAS  PubMed  Google Scholar 

  19. Rosania GR, Chang YT, Perez O, Sutherlin D, Dong HL, Lockhart DJ, Schultz PG (2000) Myoseverin, a microtubule-binding molecule with novel cellular effects. Nat Biotechnol 18:304–308

    Article  CAS  PubMed  Google Scholar 

  20. Cocuzza AJ, Chidester DR, Culp S, Fitzgerald L, Gilligan P (1999) Use of the Suzuki reaction for the synthesis of aryl-substituted heterocycles as corticotropin-releasing hormone (CRH) antagonists. Bioorg Med Chem Lett 9(7):1063–1066

    Article  CAS  PubMed  Google Scholar 

  21. Michal Hocek, Ivan Votruba, Hana Dvoráková (2003) Synthesis of carba-analogues of myoseverin by regioselective cross-coupling reactions of 2,6-dichloro-9-isopropyl purine. Tetrahedron 59:607–611

    Article  Google Scholar 

  22. Schweitzcr BA, Kool ET (1994) Nonpolar aromatic nucleosides as hydrophobic isosteres of DNA nucleosides. J Org Chem 59:7238–7242

    Article  Google Scholar 

  23. Pathak AK, Pathak V, Seitz LE, Suling WJ, Reynolds RC (2004) Antimycobacterial Agents. 1. Thio Analogues of Purine. J Med Chem 47:273–276

    Article  CAS  PubMed  Google Scholar 

  24. Basappa MS, Sugahara KN, Lee CM, ten Dam GB, van Kuppevelt TH, Miyasaka M, Yamada S, Sugahara K (2009) Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells. Glycobiology 19(7):735–742

    Article  CAS  PubMed  Google Scholar 

  25. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by World Bank under Technical Education Quality Improvement Programme (TEQUIP). SNS thank Prof. Sudhir Krishna, National Center for Biological Sciences (NCBS) for help related to biological studies. Basappa thanks Prof. K. Sugahara (Hokkaido University, JAPAN) for providing the facility and JSPS for the post doctoral fellowship. Amit G acknowledges NCBS (TIFR) for postdoctoral fellowship. SNS express his sincere gratitude to JSS Mahavidyapeetha and Dr. B.G. Sangameshwara for the encouragement towards this research work. We gratefully acknowledge Dr. Pooja Grover, Dr. Kavitha and Dr. Vinaya for critically reading the manuscript.

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Correspondence to Kanchugarakoppal S. Rangappa, B. S. Priya or S. Nanjunda Swamy.

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Raghu Ningegowda and Amit Grover contributed equally to the work.

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Ningegowda, R., Grover, A., Basappa et al. Synthesis, characterization and in vitro anti-tumor activities of novel 9-ethyl-9H-purine derivatives. Invest New Drugs 28, 754–765 (2010). https://doi.org/10.1007/s10637-009-9309-6

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