Synthesis And Anticancer Evaluation Of Some Novel Fused Pyrazolopyrimidine Derivatives.
Volume 3 - Issue 8, August 2019 Edition
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A.Y. Hassan, N.M. Saleh, Mona. S. Kadh, E.S. Abou-Amra
anticancer activity, pyrazolopyrimidopyrimidine, pyrazolopyridopyrimidine.
A new pyrazolopyrimidine formimidate 2b, pyrazolopyrimidopyrimidine (3b, 4b, 5a), pyrazolopyrimidine formamide 6b and pyrazolopyridopyrimidine 7b derivatives were designed and prepared via reaction of substituted pyrazolo[1,5-a] pyrimidine-6-carbonitrile (1a, b) with triethyl orthoformate, formamide, urea, formic and malononitrile in different conditions. The structures of target compounds were confirmed by elemental analyses and spectral data. Four of the newly synthesized compounds were selected by the NCI – Maryland-U.S.A. and were tested for their anticancer activity in an initial single high dose in the full NCI 60 cell line panel.
 I. Abdou, A. Saleh, & H. Zohdi, “Synthesis and Antitumor Activity of 5-Trifluoromethyl-2,4- dihydropyrazol-3-one Nucleosides,’’ Molecules, 9(3), 109–116, 2004.
 M. M. Ghorab, Z. H. Ismail, S. M. Abdel-Gawad, & A. A. Aziem, “Antimicrobial activity of amino acid, imidazole, and sulfonamide derivatives of pyrazolo[3,4-d]pyrimidine,’’ Heteroatom Chemistry, 15(1), 57–62, 2004.
 A. Zask, J. C. Verheijen, K. Curran, J. Kaplan, D. J. Richard, P. Nowak, D.J. Malwitz, N. Brooijmans, J. Bard, K. Svenson, J. Lucas, L. Toral-Barza,, W.G. Zhang, I. Hollander, J.J. Gibbons, R.T. Abraham, S. Ayral-Kaloustian, T.S. Mansour, K. Yu, “ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines,’’ Journal of Medicinal Chemistry, 52(16), 5013–5016, 2009.
 K. Curran, JC. Verheijen, J. Kaplan, DJ. Richard, L. Toral-Barza, I. Hollander, J. Lucas, S. Ayral-Kaloustian, K. Yu, A. Zask, “Pyrazolopyrimidines as highly potent and selective, ATPcompetitive inhibitors of the mammalian target of rapamycin(mTOR): optimization of the 1-substituent,’’ Bioorganic & Medicinal Chemistry Letters, 20:1440–1444, 2010.
 S. Alcaro, A. Artese, M. Botta, A.T. Zizzari, F. Orallo, F. Ortuso, S. Schenone, C. Brullo, M. Yáñez, “Hit Identification and Biological Evaluation of Anticancer Pyrazolopyrimidines Endowed with Anti-inflammatory Activity,’’ Chemical of Medicinal Chemistry, 5(8), 1242–1246, 2010.
 S. Kumar, & B. Narasimhan, “Therapeutic potential of heterocyclic pyrimidine scaffolds’’ Chemistry Central Journal, 12(1)2018.
 M. E. Fraley, W. F. Hoffman, R. S. Rubino, R.W. Hungate, A.J. Tebben, R. Z. Rutledge, R. C. McFall, W. R. Huckle, R.L. Kendall, K.E. Coll, K.A. Thomas, “Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors,’’ Bioorganic & Medicinal Chemistry Letters, 12:2767–2770, 2002.
 M. E. Fraley, R. S. Rubino, W. F. Hoffman, S. R. Hambaugh, K. L. Arrington, R. W. Hungate, M. T. Bilodeau, A. J. Tebben, R. Z. Rutledge, R. L. Kendall, R.C. McFall, W.R. Huckle, K.E. Coll, K.A. Thomas, “Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics,’’ Bioorganic & Medicinal Chemistry Letters, 12:3537–3541, 2003.
 C. Almansa, A. F. de Arriba, F.L. Cavalcanti, L.A. Gómez, A. Miralles, M. Merlos, J. Forn, “Synthesis and SAR of a New Series of COX-2-Selective Inhibitors: Pyrazolo[1,5-a]pyrimidine,” Journal of Medicinal Chemistry, 44(3), 350–36,2001.
 Y.D. Wang, E. Honores, B. Wu, S. Johnson, D. Powell, M. Miranda, G. Krishnamurthy, “ Synthesis, SAR study and biological evaluation of novel pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as anti-proliferative agents,” Bioorganic & Medicinal Chemistry, 17(5), 2091–2100, 2009.
 A. Kamal, J.R. Tamboli, V.L. Nayak, S.F. Adil, M. V. P. S. Vishnuvardhan & S. Ramakrishna, “Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents,’’ Bioorganic & Medicinal Chemistry Letters, 23(11), 3208–3215,2013.
 K. Paruch, M.P. Dwyer, C. Alvarez, C. Brown, T.-Y. Chan, R.J. Doll, T.J. Guzi, “Pyrazolo[1,5-a]pyrimidines as orally available inhibitors of cyclin-dependent kinase 2. Bioorg,” Medicinal Chemistry Letters, 17(22), 6220–6223, 2007.
 Z. Wu, M. E. Fraley, M.T. Bilodeau, M.L. Kaufman, E.S. Tasber, A.E. Balitza, K.A. Thomas, “Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR,’’ Bioorganic & Medicinal Chemistry Letters, 14(4), 909–912, 2004.
 A. Arora, “Role of Tyrosine Kinase Inhibitors in Cancer Therapy,” Journal of Pharmacology and Experimental Therapeutics, 315(3), 971–979, 2005.
 L. Meijer & E. Raymond, “Roscovitine and Other Purines as Kinase Inhibitors. From Starfish Oocytes to Clinical Trials,” Accounts of Chemical Research, 36(6), 417–425,2003.
 C.Y. Ishak, N.H. Metwally, H.I. Wahbi, “In vitro antimicrobial and antifungal activity of pyrimidine and pyrazolo[1,5-a]pyrimidine,” International Journal of Pharmaceutical and Phytopharmacological Research, 2(6), 407–411,2013. https://pmindexing.com/journals/ index.php/IJPPR/article/view/66(accessed June 15, 2016).
 A. Monks, D, Scudiero, P. Skehan, R, Shoemaker, K. Paull, D. Vistica, H. Curtis, L. John, C. Paul, V-W. Anne, G-G. Marcia, C. Hugh, M. Joseph & M. Boyd,“Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines’’ JNCI Journal of the National Cancer Institute, 83(11), 757–766, 1991.