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Anticancer activities of some newly synthesized pyrazole and pyrimidine derivatives

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Abstract

A series of pyrazolopyridine and pyridopyrimidine derivatives 26 were newly synthesized using 3,5-bisarylmethylene-1-methylpiperidone as the starting material. The anticancer activities of the synthesized compounds were evaluated using 59 different human tumor cell lines, representing cancers of CNS, ovary, renal, breast, colon, lung, leukemia, and melanoma, prostate as well as kidney. Some of the tested compounds, especially those with a fluorine substituent at the para-position in the phenyl ring and those with a pyridopyrimidine-2-thione with a free –NH or –SH, exhibited greater in vitro anti-tumor activities at low concentrations (log 10 [GI50] = −4.6) against the human tumor cell lines. Additionally, some of the compounds had moderate inhibitory effects on the growth of the cancer cell lines. The detailed synthesis, spectroscopic data and antitumor properties of the synthesized compounds are reported.

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Scheme 1

References

  1. Abd El-Salam, O.I., A.F.M. Fahmy, A.M. Mohamed, D.H. Elnaggar, and A.G. Hammam. 2010. Synthesis, anticancer and anti-inflammatory activities of 3,4-dihydro-7-nitrobenzo[b]oxepin-5(2H)-one and its related derivatives. World Journal of Chemistry 5: 7–17.

  2. Abdel-Hafez, N.A., A.M. Mohamed, A.E. Amr, and M.M. Abdalla. 2009. Antiarrhythmic activities of some newly synthesized tricyclic and tetracyclic thienopyridine derivatives. Scientia Pharmaceutica 77: 539–553.

  3. Agarwal, A., K. Srivastava, S.K. Puri, and P.M. Chauhan. 2005. Synthesis of 2,4,6-trisubstituted pyrimidines as antimalarial agents. Bioorganic & Medicinal Chemistry 13: 4645–4650.

  4. Ally, M.C., D.A. Scudiero, P.A. Monks, M.L. Hursey, M.J. Czerwinski, D.A. Fine, B.J. Abbott, J.G. Mayo, R.H. Shoemaker, and M.R. Boyd. 1988. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Research 48: 589–601.

  5. Amr, A.E., A.M. Mohamed, and A.A. Ibrahim. 2003. Synthesis of some new chiral tricyclic and macrocyclic pyridine derivatives as antimicrobial agents. Zeitschrift für Naturforschung 58b: 861–868.

  6. Amr, A.E., A.M. Mohamed, S.F. Mohamed, N.A. Abdel-Hafez, and A.G. Hammam. 2006. Anticancer activities of some newly synthesized pyridine, pyrane, and pyrimidine derivatives. Bioorganic & Medicinal Chemistry 14: 5481–5488.

  7. Atwal, K. 1988. Preparation of 2-amino dihydropyrimidine-5-carboxylates as cardiovascular agents. U.S. Patent 4769371, Sept. 6.

  8. Bhatt, J.J., B.R. Shah, H.B. Shah, P.B. Trivedi, N.K. Undavia, and N. Desai. 1994. Synthesis of anti-HIV, anticancer and antitubercular 4-oxo-thiazolidines (III), 2-imino-4-oxo-thiazolidines(VI) and their 5-arylidine derivatives. Indian Journal of Chemistry 33B: 189–192.

  9. Boy, M.R., and K.D. Paull. 1995. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Development Research 34: 91–109.

  10. Capdeville, R., E. Buchdunger, J. Zimmermann, and A. Matter. 2002. Glivec (ST1571, imatinib), a rationally developed, targeted anticancer drug. Nature Reviews Drug Discovery 1: 493–502.

  11. Chang, L.C.W., R.F. Spanjersberg, J.K. von Frijtag Drabbe Kunzel, T.G. van den Hout Mulder-Krieger, M.W. Beukers, J. Brussee, A.P. Jzerman. 2004. 2,4,6-Trisubstituted pyrimidines as a new class of selective adenosine A1 receptor antagonists. Journal of Medicinal Chemistry 47: 6529–6540.

  12. Chen, Y.L. 1995. Pyrazolo- and pyrazolopyridines useful as CRF antagonists, international patent WO 9534563 A1. Chemical Abstracts 124: 232447.

  13. Elnagdi, M.H., M.R.H. Elmoghayar, and G.E.H. Elgemeie. 1987. Chemistry of pyrazolopyrimidines. Advances in Heterocyclic Chemistry 41: 319–376.

  14. Elnagdi, M.H., M.R.H. Elmoghayar, and K.U. Sadek. 1990. Chemistry of Pyrazoles condensed to heteroaromatic five- and six-membered rings. Advances in Heterocyclic Chemistry 48: 223–299.

  15. El-Sayed, W.A., F.A. El-Essawy, O.M. Ali, A.M. Barsis, and A.A.-H. Abdel-Rahman. 2010a. Synthesis and antiviral evaluation of new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their acyclic nucleoside analogues. Monatshefte für Chemie 141: 1021–1028.

  16. El-Sayed, W.A., O.M. Ali, S.R. Abd El-Hamid, and A.A.-H. Abdel-Rahman. 2010b. Synthesis and antimicrobial activity of new substituted 1,2,4-triazoles and their acyclic C-nucleoside analogues. Zeitschrift für Naturforschung 5C: 15–22.

  17. Gadhachanda, V.R., B. Wu, Z. Wang, K.L. Kuhen, J. Caldwell, H. Zondler, H. Walter, M. Havenhand, and Y. He. 2007. 4-Aminopyrimidines as novel HIV-1 inhibitors. Bioorganic & Medicinal Chemistry Letters 17: 260–265.

  18. Grever, M.R., S.A. Schepartz, and B.A. Chabner. 1992. The National Cancer Institute: Cancer drug discovery and development program. Seminars in Oncology 19: 622–638.

  19. Hardy, C.R. 1984. The chemistry of pyrazolopyridines. Advances in Heterocyclic Chemistry 36: 343–409.

  20. Henry, G.D. 2004. De novo synthesis of substituted pyridines. Tetrahedron 60: 6043–6061.

  21. Joule, J.A., G. Smith, K. Mills. 1995. Heterocyclic chemistry, 3rd ed, 72–119. London: Chapman and Hall.

  22. Lyles, G.G., J.J. Dziark, and J. Connor. 1974. Structure of a dimeric piperidone–aldehyde condensation product. Tetrahedron 29: 4039–4044.

  23. Matloobi, M.C., and O. Kappe. 2007. Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives. Journal of Combinatorial Chemistry 9: 275–284.

  24. Mallea, M., A. Mahamoud, J. Chevalier, S. Alibert-Franco, P. Brouant, J. Barbe, and J.M. Pages. 2003. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates. The Biochemical Journal 376: 801–805.

  25. Mcelvain, S.M., and R. Kurt. 1948. Piperidine derivatives. XVIII. The condensation of aromatic aldehydes with 1-methyl-4-piperidone. Journal of the American Chemical Society 70: 1820–1825.

  26. McKennon, M.J., J.P. Klein, M. Coon. 2004. Pyridopyrimidine compounds and their uses. US patent 6,825,180 B2.

  27. Millet, J., M. Torrentino-Mdamet, S. Alibert, C. Rogier, C. Santelli-Rouvier, J. Mosnier, E. Baret, J. Barbe, D. Parzy, and B. Pradines. 2004. Dihydroethanoanthracene derivatives as in vitro malarial chloroquine resistance reversal agents. Antimicrobial Agents and Chemotherapy 48: 2753–2756.

  28. Mohamed, A.M., A.E. Amr, M.A. Alsharari, H.R.M. Al-Qalawi, and M.O. Germoush. 2011. Anticancer activities of some new synthesized thiazolo[3,2-a]pyrido[4,3-d] pyrimidine derivatives. American Journal of Biochemistry and Biotechnology 7(2): 43–54.

  29. Nasr, M.N.A., and S.A. Said. 2003. Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents. Archives of Pharmaceutical and Medicinal Chemistry 336: 551–559.

  30. Newlander, K.A., C.A. Parrich. 2010. Pyridopyrimidine as P13 kinase inhibitors. 2010/020222 A1.

  31. Orth, R.E. 1968. Biologically active pyrazoles. Journal of Pharmaceutical Sciences 57: 537–556.

  32. Ozeki, K., T. Ichikawa, H. Takehara, K. Tanimura, M. Sato, and H. Yaginuma. 1989. Studies on antiallergy agents. III. Synthesis of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids and related compounds. Chemical & Pharmaceutical Bulletin 37: 1780–1787.

  33. Quiroga, J., S. Cruz, B. Insuasty, and R. Abonia. 2001. Synthesis and structural analysis of 5-cyanodihydropyrazolo[3,4-b]pyridines. Journal of Heterocyclic Chemistry 38: 53–60.

  34. Quiroga, J., M. Alvarado, B. Insuasty, and R. Moreno. 1999. Synthesis of 5-cyanopyrazolo[3,4-b]pyridines in the reaction of 5-amino-3-methyl-1-phenylpyrazole with arylidene derivatives of malonodinitrile and ethyl cyanoacetate. Journal of Heterocyclic Chemistry 36: 1311–1316.

  35. Rashad, A.E., W.A. El-Sayed, A.M. Mohamed, and M.M. Ali. 2010. Synthesis of new quinoline derivatives as inhibitors of human tumor cells growth. Archiv der Pharmazie Chemistry in Life Sciences 8: 440–448.

  36. Selvam, T. P., C. R. James, P. V. Dniandev, and S. K. Valzita. 2012. A mini review of pyrimidine and fused pyrimidine marketed drugs. Research in Pharmacy 2: 01–09.

  37. Turan-Zitouni, G., P. Chevallet, F.S. Kilic, and K. Erol. 2000. Synthesis of some thiazolyl–pyrazoline derivatives and preliminary investigation of their hypotensive activity. European Journal of Medicinal Chemistry 35: 635–641.

  38. Turan-Zitouni, G., A. Ozdemir, and K. Guven. 2005. Synthesis of some 1-[(N,N-disubstitutedthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2 pyrazoline derivatives and investigation of their antibacterial and antifungal activities. Archiv der Pharmazie Pharmaceutical and Medicinal Chemistry 338: 96–104.

  39. Vacher, B., B. Bonnaud, P. Funes, N. Jubault, W. Koek, M.B. Assie, C. Cosi, and M. Kleven. 1999. Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. Journal of Medicinal Chemistry 42: 1648–1660.

  40. Zaki, M.E.A., H.A. Soliman, O.A. Hiekal, and A.E.Z. Rashad. 2006. Pyrazolopyranopyrimidines as a class of anti inflammatory agents. Zeitschrift für Naturforschung 61c: 1–5.

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Acknowledgments

The author thanks the United States National Institute of Health (NIH)/National Cancer Institute (NCI) and specially Dr. V. L. Narayanan and his team, for the inhibition of tumor growth measurements reported in this paper.

Author information

Correspondence to Ashraf M. Mohamed or Weal A. El-Sayed.

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Mohamed, A.M., El-Sayed, W.A., Alsharari, M.A. et al. Anticancer activities of some newly synthesized pyrazole and pyrimidine derivatives. Arch. Pharm. Res. 36, 1055–1065 (2013). https://doi.org/10.1007/s12272-013-0163-x

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Keywords

  • N-methylpiperidone
  • Pyrimidine derivatives
  • Human tumor
  • Anticancer activities