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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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Research Article

Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity

Author(s): Amany S. Mostafa*, Waleed A. Bayoumi, Mohamed El-Mesery and Abdelaziz Elgaml

Volume 19, Issue 3, 2019

Page: [310 - 322] Pages: 13

DOI: 10.2174/1871520618666180717125906

Price: $65

Abstract

Background: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity.

Methods: All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay.

Result: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively.

Conclusion: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.

Keywords: Anticancer, dihydropyrimidin-2(1H)-ones, docking, MTT assay, synthesis, VEGFR-2 inhibitors.

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[1]
Carmeliet, P.; Jain, R.K. Angiogenesis in cancer and other diseases. Nature, 2000, 407, 249-257.
[2]
La Montagne, K.R.; Butler, J.; Borowski, V.B.; Fuentes-Pesquera, A.R.; Blevitt, J.M.; Huang, S.; Li, R.; Connolly, P.J.; Greenberger, L.M. A highly selective, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor has potent activity in vitro and in vivo. Angiogenesis, 2009, 12, 287-296.
[3]
Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996, 86, 353-364.
[4]
Risau, W. Mechanisms of angiogenesis. Nature, 1997, 386, 671-674.
[5]
Ugale, V.G.; Patel, H.M.; Surana, S.J. Molecular modeling studies of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors using pharmacophore based 3D QSAR and docking approach. Arab. J. Chem., 2017, 10, S1980-S2003.
[6]
Musumeci, F.; Radi, M.; Brullo, C.; Schenone, S. Vascular Endothelial Growth Factor (VEGF) receptors: Drugs and new inhibitors. J. Med. Chem., 2012, 55, 10797-10822.
[7]
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, 6066-6083.
[8]
Hodous, B.L.; Geuns-Meyer, S.D.; Hughes, P.E.; Albrecht, B.K.; Bellon, S.; Caenepeel, S.; Cee, V.J.; Chaffee, S.C.; Emery, M.; Fretland, J.; Gallant, P.; Gu, Y.; Johnson, R.E.; Kim, J.L.; Long, A.M.; Morrison, M.; Olivieri, P.R.; Patel, V.F.; Polverino, A.; Rose, P.; Wang, L.; Zhao, H. Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 2886-2889.
[9]
Oguro, Y.; Miyamoto, N.; Okada, K.; Takagi, T.; Iwata, H.; Awazu, Y.; Miki, H.; Hori, A.; Kamiyama, K.; Imamura, S. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo [3,2-d]pyrimidine derivatives: Novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. Bioorg. Med. Chem., 2010, 18, 7260-7273.
[10]
Gangjee, A.; Kurup, S.; Ihnat, M.A.; Thorpe, J.E.; Shenoy, S.S. Synthesis and biological activity of N-4-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d] pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents. Bioorg. Med. Chem., 2010, 18, 3575-3587.
[11]
Egert-Schmidt, A.M.; Dreher, J.; Dunkel, U.; Kohfeld, S.; Preu, L.; Weber, H.; Ehlert, J.E.; Mutschler, B.; Totzke, F.; Schächtele, C.; Kubbutat, M.H.G.; Baumann, K.; Kunick, C. Identification of 2-anilino-9-methoxy-5,7-dihydro-6 H -pyrimido[5,4- d ][1]benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation. J. Med. Chem., 2010, 53, 2433-2442.
[12]
Hughes, T.V.; Emanuel, S.L.; Beck, A.K.; Wetter, S.K.; Connolly, P.J.; Karnachi, P.; Reuman, M.; Seraj, J.; Fuentes-Pesquera, A.R.; Gruninger, R.H.; Middleton, S.A.; Lin, R.; Davis, J.M.; Moffat, D.F.C. 4-Aryl-5-cyano-2-aminopyrimidines as VEGFR-2 inhibitors: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2007, 17, 3266-3270.
[13]
Gaudette, F.; Raeppel, S.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Macleod, A.R.; Besterman, J.M.; Vaisburg, A. Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups. Bioorg. Med. Chem. Lett., 2010, 20, 848-852.
[14]
Harris, P.A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R.M.; Davis-Ward, R.G.; Epperly, A.H.; Hinkle, K.W.; Hunter, R.N.; Johnson, J.H.; Knick, V.B.; Laudeman, C.P.; Luttrell, D.K.; Mook, R.A.; Nolte, R.T.; Rudolph, S.K.; Szewczyk, J.R.; Truesdale, A.T.; Veal, J.M.; Wang, L.; Stafford, J.A. Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J. Med. Chem., 2008, 51, 4632-4640.
[15]
Prashantha Kumar, B.R.; Sankar, G.; Nasir Baig, R.B.; Chandrashekaran, S. Novel biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study. Eur. J. Med. Chem., 2009, 44, 4192-4198.
[16]
Tale, R.H.; Rodge, A.H.; Hatnapure, G.D.; Keche, A.P.; Patil, K.M.; Pawar, R.P. The synthesis, anti-inflammatory and antimicrobial activity evaluation of novel thioanalogs of 3,4-dihydrothiopyrimidin-2(1H)-one derivatives of N-aryl urea. Med. Chem. Res., 2012, 21, 4252-4260.
[17]
Sedaghati, B.; Fassihi, A.; Arbabi, S.; Ranjbar, M.; Memarian, H.R.; Saghaie, L.; Omidi, A.; Sardari, A.; Jalali, M.; Abedi, D. Synthesis and antimicrobial activity of novel derivatives of Biginelli pyrimidines. Med. Chem. Res., 2012, 21, 3973-3983.
[18]
Tale, R.H.; Rodge, A.H.; Hatnapure, G.D.; Keche, A.P. The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: Synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation. Bioorg. Med. Chem. Lett., 2011, 21, 4648-4651.
[19]
Jalali, M.; Mahdavi, M.; Memarian, H.R.; Ranjbar, M.; Soleymani, M.; Fassihi, A.; Abedi, D. Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-one. Res. Pharm. Sci., 2012, 7, 243-247.
[20]
Chiang, A.N.; Valderramos, J.C.; Balachandran, R.; Chovatiya, R.J.; Mead, B.P.; Schneider, C.; Bell, S.L.; Klein, M.G.; Huryn, D.M.; Chen, X.S.; Day, B.W.; Fidock, D.A.; Wipf, P.; Brodsky, J.L. Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg. Med. Chem., 2009, 17, 1527-1533.
[21]
Trivedi, A.R.; Bhuva, V.R.; Dholariya, B.H.; Dodiya, D.K.; Kataria, V.B.; Shah, V.H. Novel dihydropyrimidines as a potential new class of antitubercular agents. Bioorg. Med. Chem. Lett., 2010, 20, 6100-6102.
[22]
Priya, N.; Singh, P.; Bhatia, S.; Medhi, B.; Prasad, A.K.; Parmar, V.S.; Raj, H.G. Characterization of a unique dihydropyrimidinone, ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5- carboxylate, as an effective antithrombotic agent in a rat experimental model. J. Pharm. Pharmacol., 2011, 63, 1175-1185.
[23]
Alam, O.; Khan, S.A.; Siddiqui, N.; Ahsan, W.; Verma, S.P.; Gilani, S.J. Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation. Eur. J. Med. Chem., 2010, 45, 5113-5119.
[24]
Atwal, K.S.; Rovnyak, G.C.; Kimball, S.D.; Floyd, D.M.; Moreland, S.; Swanson, B.N.; Gougoutas, J.Z.; Schwartz, J.; Smillie, K.M.; Malley, M.F. Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J. Med. Chem., 1990, 33, 2629-2635.
[25]
Nagarathnam, D.; Miao, S.W.; Lagu, B.; Chiu, G.; Fang, J.; Murali Dhar, T.G.; Zhang, J.; Tyagarajan, S.; Marzabadi, M.R.; Zhang, F.; Wong, W.C.; Sun, W.; Tian, D.; Wetzel, J.M.; Forray, C.; Chang, R.S.L.; Broten, T.P.; Ransom, R.W.; Schorn, T.W.; Chen, T.B.; O’Malley, S.; Kling, P.; Schneck, K.; Bendesky, R.; Harrell, C.M.; Vyas, K.P.; Gluchowski, C. Design and synthesis of novel α 1 a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J. Med. Chem., 1999, 42, 4764-4777.
[26]
Barrow, J.C.; Nantermet, P.G.; Selnick, H.G.; Glass, K.L.; Rittle, K.E.; Gilbert, K.F.; Steele, T.G.; Homnick, C.F.; Freidinger, R.M.; Ransom, R.W.; Kling, P.; Reiss, D.; Broten, T.P.; Schorn, T.W.; Chang, R.S.; O’Malley, S.S.; Olah, T.V.; Ellis, J.D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha (1A) receptor antagonists for the treatment of benign prostatic hyperplasia. J. Med. Chem., 2000, 43, 2703-2718.
[27]
Yoon, S.Y.; Choi, J.E.; Huh, J.W.; Hwang, O.; Lee, H.S.; Hong, H.N.; Kim, D. Monastrol, a selective inhibitor of the mitotic kinesin Eg5, induces a distinctive growth profile of dendrites and axons in primary cortical neuron cultures. Cell Motil. Cytoskeleton, 2005, 60, 181-190.
[28]
Maliga, Z.; Kapoor, T.M.; Mitchison, T.J. Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5. Chem. Biol., 2002, 9, 989-996.
[29]
Guido, B.C.; Ramos, L.M.; Nolasco, D.O.; Nobrega, C.C.; Andrade, B.Y.G.; Pic-Taylor, A.; Neto, B.A.D.; Corrêa, J.R. Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features. BMC Cancer, 2015, 15, 283.
[30]
Matsuno, K.; Sawada, J.; Sugimoto, M.; Ogo, N.; Asai, A. Bis (hetero) aryl derivatives as unique kinesin spindle protein inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 1058-1061.
[31]
DeBonis, S.; Skoufias, D.A.; Indorato, R.L.; Liger, F.; Marquet, B.; Laggner, C.; Joseph, B.; Kozielski, F. Structure-activity relationship of S-trityl-l-cysteine analogues as inhibitors of the human mitotic kinesin Eg5. J. Med. Chem., 2008, 51, 1115-1125.
[32]
Romagnoli, R.; Baraldi, P.G.; Cruz-Lopez, O.; Lopez Cara, C.; Carrion, M.D.; Brancale, A.; Hamel, E.; Chen, L.; Bortolozzi, R.; Basso, G.; Viola, G. Synthesis and antitumor activity of 1,5-disubstituted 1,2,4-triazoles as cis-restricted combretastatin analogues. J. Med. Chem., 2010, 53, 4248-4258.
[33]
Al-Soud, Y.A.; Al-Masoudi, N.A.; Ferwanah, A.S. Synthesis and properties of new substituted 1,2,4-triazoles: Potential antitumor agents. Bioorg. Med. Chem., 2003, 11, 1701-1708.
[34]
Tiwari, A.; Gopalan Kutty, N.; Kumar, N.; Chaudhary, A.; Vasanth Raj, P.; Shenoy, R.; Mallikarjuna Rao, C. Synthesis and evaluation of selected 1,3,4-oxadiazole derivatives for in vitro cytotoxicity and in vivo anti-tumor activity. Cytotechnology, 2016, 68, 2553-2565.
[35]
Ahsan, M.; Choupra, A.; Sharma, R.; Jadav, S.; Hassan, M.; Bakht, M.; Padmaja, P.; Al-Tamimi, A.; Geesi, M. Rationale design, synthesis, cytotoxicity evaluation, and molecular docking studies of 1,3, 4-oxadiazole analogues. Anticancer. Agents Med. Chem., 2018, 18(1), 121-138.
[36]
Cocco, M.T.; Congiu, C.; Lilliu, V.; Onnis, V. Synthesis and in vitro antitumoral activity of new 3,5-dicyanopyridine derivatives. Bioorg. Med. Chem., 2007, 15, 1859-1867.
[37]
Zhang, H.Z.; Drewe, J.; Tseng, B.; Kasibhatla, S.; Cai, S.X. Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay. Bioorg. Med. Chem., 2004, 12, 3649-3655.
[38]
Vicini, P.; Incerti, M.; Doytchinova, I.A.; La Colla, P.; Busonera, B.; Loddo, R. Synthesis and antiproliferative activity of benzo[d] isothiazole hydrazones. Eur. J. Med. Chem., 2006, 41, 624-632.
[39]
Hussain, H.T.; Osama, M.; Hussain, W. Thiazolidin and Thiazan-4-ones: Synthesis, conformational analysis, antimicrobial and cytotoxic activity. Int. J. Mod. Biol. Med, 2014, 5, 65-80.
[40]
Wang, F.; Yin, H.; Yue, C.; Cheng, S.; Hong, M. Syntheses, structural characterization, in vitro cytotoxicities and DNA-binding properties of triphenylantimony di(N-oxy phthalimide) and di(N-oxy succinimide) complexes. J. Organomet. Chem., 2013, 738, 35-40.
[41]
Aliabadi, A.; Mohammadi-Farani, A.; Seydi-Kangarshahi, S.; Ahmadi, F. Discovery of 2-(1,3-dioxoisoindolin-2-Yl)-N-phenyl-acetamide derivatives as probable 15-lipoxygenase-1 inhibitors with potential anticancer effects. Farmacia, 2017, 65, 268-274.
[42]
Mostafa, A.S.; El Bialy, S.A.; Bayoumi, W.A.; Abdelal, A.M. Synthesis and in vitro activity of novel non-nucleoside derivatives as anti-HCV agents. MJPS, 2012, 27, 1-10.
[43]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[44]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbel, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83, 757-766.
[45]
Molecular Operating Environment (MOE), 2013.08; Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2017..
[46]
Slobbe, P.; Ruijter, E.; Orru, R.V.A. Recent applications of multicomponent reactions in medicinal chemistry. MedChemComm, 2012, 3, 1189-1218.
[47]
Singh, M.S.; Chowdhury, S. Recent developments in solvent-free multicomponent reactions: A perfect synergy for eco-compatible organic synthesis. RSC Adv, 2012, 2, 4547-4592.
[48]
Biginelli, P. Ueber aldehyduramide des acetessigäthers. Berichte Der Dtsch. Chem. Gesellschaft., 1891, 24, 1317-1319.
[49]
Kappe, C.O. 100 years of the blglnelll dihydropyrimidine synthesis. Tetrahedron, 1993, 49, 6937-6963.
[50]
Yu, Y.; Liu, D.; Liu, C.; Luo, G. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using chloroacetic acid as catalyst. Bioorg. Med. Chem. Lett., 2007, 17, 3508-3510.
[51]
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89, 271-277.
[52]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34, 91-109.
[53]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.
[54]
Grever, M.R.; Schepartz, S.A.; Chabner, B.A. The national cancer institute: Cancer drug discovery and development program. Semin. Oncol., 1992, 19, 622-638.

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