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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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General Review Article

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents

Author(s): Nahid Abbas*, Gurubasavaraja S.P. Matada, Prasad S. Dhiwar, Shilpa Patel and Giles Devasahayam

Volume 21, Issue 7, 2021

Published on: 21 July, 2020

Page: [861 - 893] Pages: 33

DOI: 10.2174/1871520620666200721104431

Price: $65

Abstract

The rationale behind drug design is the strategic utilization of heterocyclic fragments with specific physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved to be a privileged pharmacophore for various biological cancer targets. The anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are used in cancer chemotherapy, oncology therapeutics has various limitations, especially in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective biological targeting. In this review, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to design small molecules having a pyrimidine scaffold with high anti-cancer potential.

Keywords: Apoptosis, anti-proliferative, structural activity relationship, pyrimidine, green chemistry, synthesis, SAR.

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[1]
Rani, J.; Kumar, S.; Saini, M. Biological potential of pyrimidine derivatives in a new era. Res. Chem. Intermed., 2016, 42, 6777-6804.
[http://dx.doi.org/10.1007/s11164-016-2525-8]
[2]
Saini, M.; Congiu, C.; Onnis, V. Synthesis and antitumor evaluation of 6-thioxo-6-oxo- and 2,4-dioxopyrimidine derivatives. Farmaco, 2001, 6, 741-748.
[3]
Meneghesso, S.; Vanderlinden, E.; Stevaert, A.; McGuigan, C.; Balzarini, J.; Naesens, L. Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus. Antiviral Res., 2012, 94(1), 35-43.
[http://dx.doi.org/10.1016/j.antiviral.2012.01.007] [PMID: 22306172]
[4]
Anupama, B.; Dinda, S. Synthesis and antimicrobial activity of some new 2,4,6-trisubstituted pyrimidines. Int. J. Res. Pharm. Chem., 2012, 2, 231-236.
[5]
Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives. Farmaco, 1999, 54(9), 588-593.
[http://dx.doi.org/10.1016/S0014-827X(99)00068-3] [PMID: 10555260]
[6]
Ashour, H.M.; Shaaban, O.G.; Rizk, O.H.; El-Ashmawy, I.M. Synthesis and biological evaluation of thieno [2′,3′:4,5]pyrimido] [1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a] pyrimidines as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2013, 62, 341-351.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.003] [PMID: 23376247]
[7]
Bhalgat, C.M.; Ali, M.I. Novel pyrimidine and its triazole fused derivatives: synthesis and investigation of antioxidant and anti-inflammatory activity. Arab. J. Chem., 2014, 7, 986-993.
[http://dx.doi.org/10.1016/j.arabjc.2010.12.021]
[8]
Kumar, D.; Khan, S.I.; Tekwani, B.L.; Ponnan, P.; Rawat, D.S. 4-Aminoquinoline-pyrimidine hybrids: Synthesis, antimalarial activity, heme binding and docking studies. Eur. J. Med. Chem., 2015, 89, 490-502.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.061] [PMID: 25462261]
[9]
Selvam, T.P.; James, C.R.; Dniandev, P.V.; Valzita, S.K. A mini review of pyrimidine and fused pyrimidine marketed drugs. Res. Pharm., 2012, 2, 1-9.
[10]
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[11]
Ibrahim, P.; Spevak, W. Compounds and methods for kinase modulation, and indications therefor. U.S. Patent 20,090,286,783, 2009.
[12]
Ishikawa, T.; Banno, H.; Seto, M. Fused heterocyclic compound. US Patent 7,507,740, 2009.
[13]
Day, F.A.; Launay, D.F.; Charlton, M.H. Pyrrolo [2, 3-d] pyrimidines as inhibitors of hsp90. WO Patent 2,010,043,867, 2010.
[14]
Andrews, M.D.; Bagal, S.K.; Gibson, K.R. Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of tropomyosin-related kinases. WO Patent 2,012,137,089, 2012.
[15]
Xiao, D.; Cheng, L.; Liu, X. 2,4-Diamino-6,7-dihydro-5Hpyrrolo[2,3] pyrimidine derivatives as FAK/Pyk2 inhibitors. WO Patent 2,012,092,880, 2012.
[16]
Lori, F.; Stevens, R. Anti-proliferative substituted pyrazolo[3,4-d]pyrimidines derivatives to inhibit immune activation, virus replication and tumor growth. WO Patent 2,011,014,239, 2011.
[17]
Konakanchi, D.P.; Pula, S.R. Novel pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents. WO Patent 2,009,098,715, 2009.
[18]
Mallams, A.; Paruch, K. Novel 4-cyano, 4-amino and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridines, pyrazolo[1,5-c]pyrimidines and 2H-indazole compounds and 5-cyano, 5-amino and 5-aminomethyl derivatives of imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyrazines as cyclin dependent kinase inhibitors. US Patent 20,100,137,326, 2010.
[19]
Pechan, P.; Havlicek, L. 5,7-Disubstituted 3-isopropylpyrazolo[4,3-d]pyrimidines for use as medicaments and pharmaceutical compositions. WO Patent 2,010,139,288, 2010.
[20]
Tanaka, M.; Zhang, M.; Shokat, K. Pyrazolo pyrimidine derivatives and methods of use thereof. US Patent 20,120,065,154, 2012.
[21]
Mao, L.; Zhao, L. Pyrazolo pyrimidine derivatives and uses as anticancer agents. WO Patent 2,012,097,196, 2012.
[22]
Liang, C. mTOR selective kinase inhibitors. US Patent 20,130,072,481, 2013.
[23]
Dar, C.A.; Bivona, G.T. Substituted pyrazolo[3,4-d]pyrimidines and uses thereof. WO Patent 2,013,077,921, 2013.
[24]
Chen, W.; Loury, J. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors. WO Patent 2,013,102,059, 2013.
[25]
Pass, M. 2,4,6-Trisubstituted pyrimidines as phosphotidylinositol3-kinase inhibitors and their use in the treatment of cancer. US Patent 20,090,143,384, 2009.
[26]
Lucking, U.; Kosemund, D.; Scholz, A. Disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group. WO Patent 2,013,037,894, 2013.
[27]
Butterworth, S.; Finlay, M.; Ward, R.; Kadambar, V.; Redfearn, H. 2-(2, 4, 5- Substituted-anilin) pyrimidine derivatives as EGFR modulators useful for treating cancer. AU Patent 2,013,204,962, 2013.
[28]
Pouzet, P.; Anderskewitz, R.; Martyres, D.; Nickolaus, P.; Klinder, K. K. Heterocycle-substituted piperazino-dihydrothienopyrimidines. US Patent 20,140,107,103, 2014.
[29]
Buijnsters, A.; Verdonck, C.; Emelen, K.; Bonnet, A. 4-Aryl-2-anilino-pyrimidines as PLK kinase inhibitors. WO Patent 2,009,112,439, 2009.
[30]
Pomel, V.; Gaillard, P.; Desforges, G.; Quattropani, A. 4-Morpholino-pyrido[3,2-d]pyrimidines. US Patent 20,110,257,170, 2011.
[31]
Murthi, K.; Casaubon, R. Pyrido[2,3-d]pyrimidines and their use as kinase inhibitors. US Patent 20,110,201,594, 2011.
[32]
Routier, S. Derivatives of pyrido[3,2-d]pyrimidine, methods for preparation thereof and therapeutic uses thereof. US Patent 20,130,109,693, 2013.
[33]
Burgdorf, L.; Kuhn, D.; Ross, T.; Deutsch, C. Pyridopyrimidine derivatives as protein kinase inhibitors. WO Patent 2,014,023,385, 2014.
[34]
Bae, I.H.; Son, J.B.; Han, S.M. Thieno[3,2-d]pyrimidine derivatives having inhibitory activity for protein kinases. WO Patent 2,013,100,632, 2013.
[35]
Heckel, A.; Himmelsbach, F. Halogen or cyano-substituted thieno [2,3-d]pyrimidines having MNK1/MNK2 inhibiting activity for pharmaceutical compositions. US Patent 20,130,065,914, 2013.
[36]
Bansal, R.K. Text Book of heterocyclic Chemistry, 3rd ed.; New Age International Pvt Ltd Publishers: India, 2015.
[37]
Prachayasittikul, S.; Worachartcheewan, A.; Nantasenamat, C.; Chinworrungsee, M.; Sornsongkhram, N.; Ruchirawat, S.; Prachayasittikul, V. Synthesis and structure-activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents. Eur. J. Med. Chem., 2011, 46(2), 738-742.
[http://dx.doi.org/10.1016/j.ejmech.2010.12.009] [PMID: 21216051]
[38]
Reddy, O.; Suryanarayana, C.; Narayana, J. Synthesis and cytotoxic evaluation for some new 2,5-disubstituted pyrimidine derivatives for anticancer activity. Med. Chem. Res., 2015, 24, 1777-1788.
[http://dx.doi.org/10.1007/s00044-014-1276-6]
[39]
Fujita, F.; Fujita, M.; Inaba, H.; Sugimoto, T.; Okuyama, Y.; Taguchi, T. Antitumor activity of HO-221, a derivative of benzoylphenylurea against human cancer xenografts in nude mice. Gan To Kagaku Ryoho, 1991, 18(13), 2255-2261.
[PMID: 1929446]
[40]
Gurulingappa, H.; Amador, M.L.; Zhao, M.; Rudek, M.A.; Hidalgo, M.; Khan, S.R. Synthesis and antitumor evaluation of benzoylphenylurea analogs. Bioorg. Med. Chem. Lett., 2004, 14(9), 2213-2216.
[http://dx.doi.org/10.1016/j.bmcl.2004.02.019] [PMID: 15081011]
[41]
Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P.M.; Dhar, K.L. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids. Eur. J. Med. Chem., 2014, 77, 422-487.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.018] [PMID: 24685980]
[42]
Papadopoulou, A.A.; Katsoura, M.H.; Chatzikonstantinou, A.; Kyriakou, E.; Polydera, A.C.; Tzakos, A.G.; Stamatis, H. Enzymatic hybridization of α-lipoic acid with bioactive compounds in ionic solvents. Bioresour. Technol., 2013, 136, 41-48.
[http://dx.doi.org/10.1016/j.biortech.2013.02.067] [PMID: 23567667]
[43]
Pingaew, R.; Saekee, A.; Mandi, P.; Nantasenamat, C. Synthesis, biological evaluation and molecular docking of novel chalconecoumarin hybrids as anticancer and antimalarial agents. Eur. J. Med. Chem., 2014, 85, 65-76.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.087] [PMID: 25078311]
[44]
Karampelas, T.; Argyros, O.; Sayyad, N.; Spyridaki, K.; Pappas, C.; Morgan, K.; Kolios, G.; Millar, R.P.; Liapakis, G.; Tzakos, A.G.; Fokas, D.; Tamvakopoulos, C. GnRH-Gemcitabine conjugates for the treatment of androgen-independent prostate cancer: Pharmacokinetic enhancements combined with targeted drug delivery. Bioconjug. Chem., 2014, 25(4), 813-823.
[http://dx.doi.org/10.1021/bc500081g] [PMID: 24661240]
[45]
Kumar, S.; Kaushik, A. Molecular docking, synthesis and biological significance of pyrimidine analogues as prospective antimicrobial and antiproliferative agents. BMC Chem., 2019, 13, 85.
[http://dx.doi.org/10.1186/s13065-019-0601-z]
[46]
Nagwa, M.; Hanaa, A.; Mohamed, A. Synthesis, anticancer activity and docking study of quinoline, diazepine, pyrimidine and pyridine. IOSR-JAC, 2019, 12(3), 47-60.
[47]
Carmena, M.; Earnshaw, W.C. The cellular geography of aurora kinases. Nat. Rev. Mol. Cell Biol., 2003, 4(11), 842-854.
[http://dx.doi.org/10.1038/nrm1245] [PMID: 14625535]
[48]
Long, L.; Luo, Y.; Hou, Z.J.; Ma, H.J.; Long, Z.J.; Tu, Z.C.; Huang, L.J.; Liu, Q.; Lu, G. Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold. Eur. J. Med. Chem., 2018, 145, 805-812.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.082] [PMID: 29358147]
[49]
Qin, W.W.; Sang, C.Y.; Zhang, L.L.; Wei, W.; Tian, H.Z.; Liu, H.X.; Chen, S.W.; Hui, L. Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors. Eur. J. Med. Chem., 2015, 95, 174-184.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.044] [PMID: 25812967]
[50]
Jain, K.S.; Chitre, T.S.; Miniyar, P.B. Biological and medicinal significance of pyrimidines. Curr. Sci., 2006, 90, 793-803.
[51]
Smith, N.F.; Figg, W.D. Recent advances in pharmacogenetic approaches to anticancer drug development. Drug Dev. Res., 2004, 62, 233-253.
[http://dx.doi.org/10.1002/ddr.10361]
[52]
Prachayasittikul, S.; Sornsongkhram, N.; Pingaew, R.; Worachartcheewan, A.; Ruchirawat, S.; Prachayasittikul, V. Synthesis of N-substituted 5-iodouracils as antimicrobial and anticancer agents. Molecules, 2009, 14(8), 2768-2779.
[http://dx.doi.org/10.3390/molecules14082768] [PMID: 19701123]
[53]
Awad, S.M.; Youns, M.M.; Ahmed, N.M. Design, synthesis and biological evaluation of novel 2-thiouracil-5-sufonamide isosters as anticancer agents. Pharmacophore, 2018, 9(3), 13-24.
[54]
Motawia, M.S.; Abdel-Megied, A.E. Synthesis of 5-alkoxymethyl derivatives of 3-amino-2′,3′-dideoxyuridine and evaluation of their activity against HIV and cancer. Acta Chem. Scand. A, 1992, 46, 77-81.
[http://dx.doi.org/10.3891/acta.chem.scand.46-0077]
[55]
Fabrissin, S.; de Nardo, M.; Nisi, C.; Morasca, L.; Dolfini, E.; Franchi, G. Synthesis and anticancer activity of 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracils. J. Med. Chem., 1976, 19(5), 639-642.
[http://dx.doi.org/10.1021/jm00227a012] [PMID: 1271405]
[56]
Arikkatt, S.D.; Mathew, V.B. Pyrimidine derivatives and its biological potential-a review. Int. J. Org. Bioorg. Chem., 2014, 4, 1-5.
[57]
Khanage, S.G.; Raju, S.A.; Mohite, P.B.; Pandhare, R.B. Synthesis and pharmacological evaluation of some new pyrimidine derivatives containing 1,2,4-triazole. Adv. Pharm. Bull., 2012, 2(2), 213-222.
[PMID: 24312796]
[58]
Nassar, E. Synthesis, in vitro antitumor and antimicrobial activity of some pyrazoline, pyridine and pyrimidine derivatives linked to indole moiety. J. Am. Sci., 2010, 6, 338-347.
[59]
Prachayasittikul, S.; Sornsongkhram, N. Synthesis and novel bioactivities of substituted 6-propylthiouracils. Eur. J. Sci. Res., 2009, 36, 236-245.
[60]
Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 2002, 3(6), 415-428.
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769]
[61]
Mahlknecht, U.; Hoelzer, D. Histone acetylation modifiers in the pathogenesis of malignant disease. Mol. Med., 2000, 6(8), 623-644.
[http://dx.doi.org/10.1007/BF03402044] [PMID: 11055583]
[62]
Yoshida, M.; Kijima, M.; Akita, M.; Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by Trichostatin A. J. Biol. Chem., 1990, 265(28), 17174-17179.
[PMID: 2211619]
[63]
Richon, V.M.; Emiliani, S.; Verdin, E.; Webb, Y.; Breslow, R.; Rifkind, R.A.; Marks, P.A. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA, 1998, 95(6), 3003-3007.
[http://dx.doi.org/10.1073/pnas.95.6.3003] [PMID: 9501205]
[64]
Mai, A.; Massa, S.; Rotili, D.; Pezzi, R.; Bottoni, P.; Scatena, R.; Meraner, J.; Brosch, G. Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel uracil-based hydroxamates. Bioorg. Med. Chem. Lett., 2005, 15(21), 4656-4661.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.081] [PMID: 16165353]
[65]
Luo, G.; Tang, Z.; Lao, K.; Li, X.; You, Q.; Xiang, H. Structure-activity relationships of 2, 4-disubstituted pyrimidines as dual ERα/VEGFR-2 ligands with anti-breast cancer activity. Eur. J. Med. Chem., 2018, 150, 783-795.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.018] [PMID: 29587221]
[66]
Amin, L.H.T.; Shawer, T.Z.; El-Naggar, A.M.; El-Sehrawi, H.M.A. Design, synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors. Bioorg. Chem., 2019, 91, 103159.
[http://dx.doi.org/10.1016/j.bioorg.2019.103159] [PMID: 31382056]
[67]
Fukushima, M.; Suzuki, N.; Emura, T.; Yano, S.; Kazuno, H.; Tada, Y.; Yamada, Y.; Asao, T. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides. Biochem. Pharmacol., 2000, 59(10), 1227-1236.
[http://dx.doi.org/10.1016/S0006-2952(00)00253-7] [PMID: 10736423]
[68]
Sun, L.; Li, J.; Bera, H.; Dolzhenko, A.V.; Chiu, G.N.; Chui, W.K. Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines as thymidine phosphorylase inhibitors. Eur. J. Med. Chem., 2013, 70, 400-410.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.022] [PMID: 24177367]
[69]
Ma, L.Y.; Zheng, Y.C.; Wang, S.Q.; Wang, B.; Wang, Z.R.; Pang, L.P.; Zhang, M.; Wang, J.W.; Ding, L.; Li, J.; Wang, C.; Hu, B.; Liu, Y.; Zhang, X.D.; Wang, J.J.; Wang, Z.J.; Zhao, W.; Liu, H.M. Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents. J. Med. Chem., 2015, 58(4), 1705-1716.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00037] [PMID: 25610955]
[70]
Ma, L.Y.; Wang, B.; Pang, L.P.; Zhang, M.; Wang, S.Q.; Zheng, Y.C.; Shao, K.P.; Xue, D.Q.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole-pyrimidine-urea hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(5), 1124-1128.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.087] [PMID: 25655718]
[71]
Ma, L.Y.; Pang, L.P.; Wang, B.; Zhang, M.; Hu, B.; Xue, D.Q.; Shao, K.P.; Zhang, B.L.; Liu, Y.; Zhang, E.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole-pyrimidine hybrids as potential anticancer agents. Eur. J. Med. Chem., 2014, 86, 368-380.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.010] [PMID: 25180925]
[72]
Taher, A.T.; Helwa, A.A. Synthesis, antitumor and antimicrobial testing of some new thiopyrimidine analogues. Chem. Pharm. Bull. (Tokyo), 2012, 60(10), 1305-1313.
[http://dx.doi.org/10.1248/cpb.c12-00557] [PMID: 22863845]
[73]
Abdel-Mohsen, H.T.; Ragab, F.A.; Ramla, M.M.; El Diwani, H.I. Novel benzimidazole-pyrimidine conjugates as potent antitumor agents. Eur. J. Med. Chem., 2010, 45(6), 2336-2344.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.011] [PMID: 20356655]
[74]
Taher, A.T.; Helwa, A.A. Novel pyrimidinone derivatives: Synthesis, antitumor and antimicrobial evaluation. Chem. Pharm. Bull. (Tokyo), 2012, 60(4), 521-530.
[http://dx.doi.org/10.1248/cpb.60.521] [PMID: 22466736]
[75]
Taher, A.T.; Abou-Seri, S.M. Synthesis and bioactivity evaluation of new 6-aryl-5-cyano thiouracils as potential antimicrobial and anticancer agents. Molecules, 2012, 17(8), 9868-9886.
[http://dx.doi.org/10.3390/molecules17089868] [PMID: 22902882]
[76]
Liu, Y.M.; Chen, C.H.; Yeh, T.K.; Liou, J.P. Synthesis and evaluation of novel 7H-pyrrolo-[2,3-d]pyrimidine derivatives as potential anticancer agents. Future Med. Chem., 2019, 11(9), 959-974.
[http://dx.doi.org/10.4155/fmc-2018-0564] [PMID: 30789758]
[77]
Maher, M.; Kassab, A.E.; Zaher, A.F.; Mahmoud, Z. Novel pyrazolo[3,4-d]pyrimidines: Design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 532-546.
[http://dx.doi.org/10.1080/14756366.2018.1564046] [PMID: 30688116]
[78]
Metwally, N.H.; Mohamed, M.S.; Ragb, E.A. Design, synthesis, anticancer evaluation, molecular docking and cell cycle analysis of 3-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine derivatives as potent histone lysine demethylases (KDM) inhibitors and apoptosis inducers. Bioorg. Chem., 2019, 88, 102929.
[http://dx.doi.org/10.1016/j.bioorg.2019.102929] [PMID: 31015179]
[79]
Zask, A.; Verheijen, J.C.; Curran, K.; Kaplan, J.; Richard, D.J.; Nowak, P.; Malwitz, D.J.; Brooijmans, N.; Bard, J.; Svenson, K.; Lucas, J.; Toral-Barza, L.; Zhang, W.G.; Hollander, I.; Gibbons, J.J.; Abraham, R.T.; Ayral-Kaloustian, S.; Mansour, T.S.; Yu, K. ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. J. Med. Chem., 2009, 52(16), 5013-5016.
[http://dx.doi.org/10.1021/jm900851f] [PMID: 19645448]
[80]
Ding, Z.; Wu, C.J.; Jaskelioff, M.; Ivanova, E.; Kost-Alimova, M.; Protopopov, A.; Chu, G.C.; Wang, G.; Lu, X.; Labrot, E.S.; Hu, J.; Wang, W.; Xiao, Y.; Zhang, H.; Zhang, J.; Zhang, J.; Gan, B.; Perry, S.R.; Jiang, S.; Li, L.; Horner, J.W.; Wang, Y.A.; Chin, L.; DePinho, R.A. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell, 2012, 148(5), 896-907.
[http://dx.doi.org/10.1016/j.cell.2012.01.039] [PMID: 22341455]
[81]
Stewart, S.A.; Bertuch, A.A. The role of telomeres and telomerase in cancer research. Cancer Res., 2010, 70(19), 7365-7371.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1373] [PMID: 20841475]
[82]
Gillis, A.J.; Schuller, A.P.; Skordalakes, E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature, 2008, 455(7213), 633-637.
[http://dx.doi.org/10.1038/nature07283] [PMID: 18758444]
[83]
Sfeir, A.; Kabir, S.; van Overbeek, M.; Celli, G.B.; de Lange, T. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science, 2010, 327(5973), 1657-1661.
[http://dx.doi.org/10.1126/science.1185100] [PMID: 20339076]
[84]
Martinez, P.; Thanasoula, M.; Carlos, A.R.; Gómez-López, G.; Tejera, A.M.; Schoeftner, S.; Dominguez, O.; Pisano, D.G.; Tarsounas, M.; Blasco, M.A. Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat. Cell Biol., 2010, 12(8), 768-780.
[http://dx.doi.org/10.1038/ncb2081] [PMID: 20622869]
[85]
Kosbar, T.R.; Sofan, M.A. Synthesis, biological evaluation, and molecular docking studies of novel pyrazolo [3,4d] pyrimidines as potential telomerase inhibitors. J. Heterocycl. Chem., 2018, 55(4), 803-813.
[http://dx.doi.org/10.1002/jhet.3094]
[86]
Elmetwally, S.A.; Saied, K.F.; Eissa, I.H.; Elkaeed, E.B. Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg. Chem., 2019, 88, 102944.
[http://dx.doi.org/10.1016/j.bioorg.2019.102944] [PMID: 31051400]
[87]
Ghorab, M.M.; Alsaid, M.S. Anticancer activity of some novel thieno [2,3-d] pyrimidine derivatives. Biomed. Res., 2016, 1(27), 110-115.
[88]
Kandeel, M.M.; Mounir, A.A.; Refaat, H.M.; Kassab, A.E. Synthesis of thieno[2,3-d]pyrimidines, thieno[2,3-d]triazinones and thieno [2,3-e]diazepinones of anticipated anti-cancer activity. J. Chem. Res., 2012, 36, 105-110.
[http://dx.doi.org/10.3184/174751912X13282020691270]
[89]
Kandeel, M.M.; Mounir, A.A.; Refaat, H.M.; Kassab, A.E. Synthesis of potent anticancer thieno[2,3-d]pyrimidine derivatives. J. Chem. Res., 2012, 36, 266-275.
[http://dx.doi.org/10.3184/174751912X13333849411283]
[90]
Kandeel, M.M.; Mounir, A.A.; Refaat, H.M.; Kassab, A.E. Synthesis of effective anticancer thieno [2,3-d] pyrimidine-4-ones and thieno [3,2-e]triazolo[4,3-c]pyrimidines. Int. J. Pharm. Pharm. Sci., 2012, 4, 438-448.
[91]
Dai, Y.; Guo, Y.; Frey, R.R.; Ji, Z.; Curtin, M.L.; Ahmed, A.A.; Albert, D.H.; Arnold, L.; Arries, S.S.; Barlozzari, T.; Bauch, J.L.; Bouska, J.J.; Bousquet, P.F.; Cunha, G.A.; Glaser, K.B.; Guo, J.; Li, J.; Marcotte, P.A.; Marsh, K.C.; Moskey, M.D.; Pease, L.J.; Stewart, K.D.; Stoll, V.S.; Tapang, P.; Wishart, N.; Davidsen, S.K.; Michaelides, M.R. Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem., 2005, 48(19), 6066-6083.
[http://dx.doi.org/10.1021/jm050458h] [PMID: 16162008]
[92]
Kassab, A.E.; Gedawy, E.M. Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives. Eur. J. Med. Chem., 2013, 63, 224-230.
[http://dx.doi.org/10.1016/j.ejmech.2013.02.011] [PMID: 23501108]
[93]
Horton, D.A.; Bourne, G.T.; Smythe, M.L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev., 2003, 103(3), 893-930.
[http://dx.doi.org/10.1021/cr020033s] [PMID: 12630855]
[94]
Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep., 2004, 21(5), 650-668.
[http://dx.doi.org/10.1039/b310691h] [PMID: 15459759]
[95]
Ahmed, M.; Belal, A.; Youns, M. Design, synthesis, molecular modeling and anti-breast cancer activity of novel quinazolin-4-one derivatives linked to thiazolidinone, oxadiazole or pyrazole moieties. Med. Chem. Res., 2015, 24, 2993-3007.
[http://dx.doi.org/10.1007/s00044-015-1357-1]
[96]
Liu, J.F.; Wilson, C.J.; Ye, P.; Sprague, K.; Sargent, K.; Si, Y.; Beletsky, G.; Yohannes, D.; Ng, S.C. Privileged structure-based quinazolinone natural product-templated libraries: Identification of novel tubulin polymerization inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(3), 686-690.
[http://dx.doi.org/10.1016/j.bmcl.2005.10.022] [PMID: 16257201]
[97]
Ma, Z.; Gao, G.; Fang, K.; Sun, H. Development of novel anticancer agents with a scaffold of tetrahydropyrido [4,3-d] pyrimidine-2, 4-dione. Medicinal Chem. Lett., 2019, 16(10), 191-195.
[98]
Khalifa, N.M.; Alkahtani, H.M.; Bakheit, A.H. Kinase inhibitors of novel pyridopyrimidinone candidates: Synthesis and in-vitro anticancer properties. J. Chem., 2019, 2, 106-130.
[http://dx.doi.org/10.1155/2019/2635219]
[99]
Buron, F.; Mérour, J.Y.; Akssira, M.; Guillaumet, G.; Routier, S. Recent advances in the chemistry and biology of pyridopyrimidines. Eur. J. Med. Chem., 2015, 95, 76-95.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.029] [PMID: 25794791]
[100]
Smaill, J.B.; Gonzales, A.J.; Spicer, J.A.; Lee, H.; Reed, J.E.; Sexton, K.; Althaus, I.W.; Zhu, T.; Black, S.L.; Blaser, A.; Denny, W.A.; Ellis, P.A.; Fakhoury, S.; Harvey, P.J.; Hook, K.; McCarthy, F.O.; Palmer, B.D.; Rivault, F.; Schlosser, K.; Ellis, T.; Thompson, A.M.; Trachet, E.; Winters, R.T.; Tecle, H.; Bridges, A. Optimization of substituted quinazoline and pyrido [3, 4-d] pyrimidine derivatives as orally active, irreversible inhibitors of the epidermal growth factor receptor family. J. Med. Chem., 2016, 59(17), 8103-8124.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00883] [PMID: 27491023]
[101]
Alblewi, F.F.; Okasha, R.M.; Eskandrani, A.A.; Afifi, T.H.; Mohamed, H.M.; Halawa, A.H.; Fouda, A.M.; Al-Dies, A.M.; Mora, A.; El-Agrody, A.M. Design and synthesis of novel heterocyclic-based 4H-benzo[h]chromene moieties: Targeting antitumor caspase 3/7 activities and cell cycle analysis. Molecules, 2019, 24(6), 1060.
[http://dx.doi.org/10.3390/molecules24061060] [PMID: 30889862]
[102]
Scherbakov, A.M.; Komkov, A.V.; Komendantova, A.S.; Yastrebova, M.A. Steroidal pyrimidines and dihydrotriazines as novel classes of anticancer agents against hormone-dependent breast cancer cells. Frontiers Pharmacol., 2018, 10(8), 979.
[http://dx.doi.org/10.3389/fphar.2017.00979]
[103]
Addepalli, Y.; Yang, X.; Zhou, M.; Reddy, D.P.; Zhang, S.L.; Wang, Z.; He, Y. Synthesis and anticancer activity evaluation of novel azacalix[2]arene[2]pyrimidines. Eur. J. Med. Chem., 2018, 151, 214-225.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.079] [PMID: 29614418]
[104]
Ahmed, N.M.; Youns, M.; Soltan, M.K.; Said, A.M. Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1110-1120.
[http://dx.doi.org/10.1080/14756366.2019.1612889] [PMID: 31117890]
[105]
Burns, M.J. Towards the Total Synthesis of Phacelocarpus-2-Pyrone A: Novel 2-Pyrone Chemistry. PhD Thesis, University of York: England, 2010.
[106]
Godin, F.; Mochirian, P. Total synthesis of zincophorin methyl ester. Stereocontrol of 1,2-induction using sterically hindered enoxysilanes. Tetrahedron, 2015, 71, 709-726.
[http://dx.doi.org/10.1016/j.tet.2014.11.061]
[107]
Pfefferkorn, J.A.; Bowles, D.M. Development of a practical synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Tetrahedron, 2007, 63, 8124-8134.
[http://dx.doi.org/10.1016/j.tet.2007.06.005]
[108]
Chen, P.S. Synthesis of Heterocyclic Natural Products and Analogues; Simon Fraser University: Canada, 2012.
[109]
Brown, D.J.; Ellman, J.A. The Chemistry of Heterocyclic Compounds, Cinnolines and Phthalazines, Supplement II; John Wiley & Sons: USA, 2005, p. 27.
[110]
Pellegrino, G.; Leonetti, F. Solid phase synthesis of a molecular library of pyrimidines, pyrazoles, and isoxazoles with biological potential. Tetrahedron Lett., 2010, 51, 1702-1705.
[http://dx.doi.org/10.1016/j.tetlet.2010.01.089]
[111]
Gordeev, M.F.; Patel, D.V. Approaches to combinatorial synthesis of heterocycles: Solid phase synthesis of pyridines and pyrido[2,3-d]pyrimidines. Tetrahedron Lett., 1996, 37, 4643-4646.
[http://dx.doi.org/10.1016/0040-4039(96)00923-9]
[112]
Ghorbani, R.; Karimi, R. One-pot synthesis of pyrimidines under solvent-free conditions. C. R. Chim., 2014, 1, 324-330.
[http://dx.doi.org/10.1016/j.crci.2013.07.010]

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