Synthesis and In Vitro Anticancer Activity of 6-Ferrocenylpyrimidin-4(3H)-one Derivatives

Author(s): Stanislav A. Grabovskiy*, Rinat S. Muhammadiev, Lenar R. Valiullin, Ivan S. Raginov, Natalie N. Kabal'nova

Journal Name: Current Organic Synthesis

Volume 16 , Issue 1 , 2019

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Graphical Abstract:


Aim and Objective: Some ferrocenyl derivatives are active in vitro and in vivo against cancer. Generally, ferrocenyl derivatives for cancer research have three key components: a ferrocene moiety, a conjugated linker that lowers the oxidation potential and some derivative (peptide, nucleobase and others) that can interact with biomolecules. Since the pyrimidine fragment can easily pass through the membrane into the cells and become involved in metabolism; it appears to be promising. Furthermore, this fragment is an electron-acceptor group, so a spacer can be excluded. Therefore, the synthesis of 6-ferrocenylpyrimidin-4(3H)-one derivatives and the study of their anticancer activity have scientific and practical interest.

Methods: The syntheses of 6-ferrocenylpyrimidin-4(3H)-one derivatives were performed by the condensation of ethyl 3-ferrocenyl-3-oxopropionate with thiourea or acetamidine or guanidine. The cytotoxicity of four 6- ferrocenylpyrimidin-4(3H)-one derivatives was evaluated by using the MTT assay in vitro against Human breast adenocarcinoma MCF-7 and normal human skin fibroblast HSF cells. The tested derivatives induced a concentration-dependent cytotoxic response in cell lines.

Results: A study of the cytotoxic activity of 6-ferrocenylpyrimidin-4(3H)-one derivatives by the MTT test has found that all compounds have a dose-dependent toxic effect on the lines of breast cancer cells (MCF-7) and normal human fibroblast cells (HSF). The most pronounced cytotoxic effect is exhibited by 2-methyl-6-ferrocenylpyrimidin- 4(3H)-one (MCF-7, IC50 17 ± 1 µM).

Conclusion: The experimental results confirm the importance of investigation and design of ferrocenylpyrimidin- 4(3H)-one derivatives as anticancer agents. Compounds where the pyrimidine derivatives are directly linked to the ferrocene unit rather than via a spacer group also may be of interest for antiproliferative drug design.

Keywords: Ferrocene derivatives, pyrimidine, cytotoxicity, synthesis, DFT, anticancer agents.

Fiorina, V.J.; Dubois, R.J.; Brynes, S. Ferrocenyl polyamines as agents for the chemoimmunotherapy of cancer. J. Med. Chem., 1978, 21(4), 393-395.
Köpf-Maier, P.; Köpf, H.; Neuse, E.W. Ferricenium complexes: A new type of water-soluble anti-tumor agent. J. Cancer Res. Clin. Oncol., 1984, 108, 336-340.
van Staveren, D.R.; Metzler-Nolte, N. Bioorganometallic chemistry of ferrocene. Chem. Rev., 2004, 104(12), 5931-5985.
Accardo, A.; Tesauro, D.; Morelli, G. Peptide-based targeting strategies for simultaneous imaging and therapy with nanovectors. Polym. J. (Tokyo, Jpn.), 2013, 45, 481-493.
Snegur, L.V.; Babin, V.N.; Simenel, A.A.; Nekrasov, Yu.S.; Ostrovskaya, L.A.; Sergeeva, N.S.D. Antitumor activities of ferrocene compounds. Russ. Chem. Bull., 2010, 59(12), 2167-2178.
Kowalski, K.; Szczupak, Ł.; Saloman, S.; Steverding, D.; Jabłoński, A.; Vrček, V.; Hildebrandt, A.; Lang, H.; Rybarczyk-Pirek, A. Cymantrene, cyrhetrene and ferrocene nucleobase conjugates: synthesis, structure, computational study, electrochemistry and antitrypanosomal activity. ChemPlusChem, 2017, 82(2), 303-314.
Tabbì, G.; Cassino, C.; Cavigiolio, G.; Colangelo, D.; Ghiglia, A.; Viano, I.; Osella, D. Water stability and cytotoxic activity relationship of a series of ferrocenium derivatives. ESR insights on the radical production during the degradation process. J. Med. Chem., 2002, 45(26), 5786-5796.
Graf, N.; Lippard, S.J. Redox activation of metal-based prodrugs as a strategy for drug delivery. Adv. Drug Deliv. Rev., 2012, 64(11), 993-1004.
Pérez, W.I.; Soto, Y.; Ortíz, C.; Matta, J.; Meléndez, E. Ferrocenes as potential chemotherapeutic drugs: Synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay. Bioorg. Med. Chem., 2015, 23(3), 471-479.
Acevedo-Morantes, C.Y.; Meléndez, E.; Singh, S.P.; Ramírez-Vick, J.E. Cytotoxicity and reactive oxygen species generated by ferrocenium and ferrocene on MCF7 and MCF10A cell lines. J. Cancer Sci. Ther., 2012, 4(9), 271-275.
Osella, D.; Ferrali, M.; Zanello, P.; Laschi, F.; Fontani, M.; Nervi, C.; Cavigiolio, G. On the mechanism of the antitumor activity of ferrocenium derivatives. Inorg. Chim. Acta, 2000, 306(1), 42-48.
Liou, G-Y.; Storz, P. Reactive oxygen species in cancer. Free Radic. Res., 2010, 44(5), 479-496.
Zhou, D.; Shao, L.; Spitz, D.R. Reactive oxygen species in normal and tumor stem cells. Adv. Cancer Res., 2014, 122, 1-67.
Saito, S.; Lin, Y.C.; Tsai, M.H.; Lin, C.S.; Murayama, Y.; Sato, R.; Yokoyama, K.K. Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J. Med. Sci., 2015, 31(6), 279-286.
Hagen, H.; Marzenell, P.; Jentzsch, E.; Wenz, F.; Veldwijk, M.R.; Mokhir, A. Aminoferrocene-based prodrugs activated by reactive oxygen species. J. Med. Chem., 2012, 55(2), 924-934.
Acevedo-Morantes, C.Y.; Meléndez, E.; Singh, S.P.; Ramírez-Vick, J.E. Cytotoxicity and reactive oxygen species generated by ferrocenium and ferrocene on MCF7 and MCF10A cell lines. J. Cancer Sci. Ther., 2012, 4(9), 271-275.
Ornelas, C. Application of ferrocene and its derivatives in cancer research. New J. Chem., 2011, 35(10), 1973-1985.
Corry, A.J.; Goel, A.; Alley, S.R.; Kelly, P.N.; O’Sullivan, D.; Savage, D.; Kenny, P.T.M. N-ortho-Ferrocenyl benzoyl dipeptide esters: Synthesis, structural characterization and in vitro anti-cancer activity of N-ortho-(ferrocenyl)benzoyl-glycine-l-alanine ethyl ester and N-ortho-(ferrocenyl)benzoyl-l-alanine-glycine ethyl ester. J. Organomet. Chem., 2007, 692(6), 1405-1410.
Goel, A.; Savage, D.; Alley, S.R.; Kelly, P.N.; O’Sullivan, D.; Mueller-Bunz, H.; Kenny, P.T.M. The synthesis and structural characterization of novel N-meta-ferrocenyl benzoyl dipeptide esters: The X-ray crystal structure and in vitro anti-cancer activity of N-meta-ferrocenyl)benzoyl-l-alanine-glycine ethyl ester. J. Organomet. Chem., 2007, 692(6), 1292-1299.
Mooney, A.; Corry, A.J.; O’Sullivan, D.; Rai, D.K.; Kenny, P.T.M. The synthesis, structural characterization and in vitro anti-cancer activity of novel N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters and novel N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters. J. Organomet. Chem., 2009, 694(6), 886-894.
Mooney, A.; Corry, A.J.; Ruairc, C.N.; Mahgoub, T.; O’Sullivan, D.; O’Donovan, N.; Crown, J.; Varughese, S.; Draper, S.M.; Rai, D.K.; Kenny, P.T.M. Synthesis, characterisation and biological evaluation of N-(ferrocenyl)naphthoyl amino acid esters as anticancer agents. Dalton Trans., 2010, 39, 8228-8239.
Meunier, P.; Ouattara, I.; Gautheron, B.; Tirouflet, J.; Camboli, D.; Besançon, J. Synthèe, caractérisation et propriétés cytotoxiques des premiers ‘métallocénonucléosides’. Eur. J. Med. Chem., 1991, 26(3), 351-362.
Simenel, A.A.; Morozova, E.A.; Snegur, L.V.; Zykova, S.I.; Kachala, V.V.; Ostrovskaya, L.A.; Bluchterova, N.V.; Fomina, M.M. Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo. Appl. Organomet. Chem., 2009, 23(6), 219-224.
Simenel, A.A.; Dokuchaeva, G.A.; Snegur, L.V.; Rodionov, A.N.; Ilyin, M.M.; Zykova, S.I.; Ostrovskaya, L.A.; Bluchterova, N.V.; Fomina, M.M.; Rikova, V.A. Ferrocene‐modified thiopyrimidines: synthesis, enantiomeric resolution, antitumor activity. Appl. Organomet. Chem., 2011, 25(70), 70-75.
Top, S.; Thibaudeau, C.; Vessières, A.; Brulé, E.; Le Bideau, F.; Joerger, J-M.; Plamont, M-A.; Samreth, S.; Edgar, A.; Marrot, J.R.M.; Herson, P.; Jaouen, G. Synthesis and structure activity relationship of organometallic steroidal androgen derivatives. Organometallics, 2009, 28(5), 1414-1424.
Manosroi, J.; Rueanto, K.; Boonpisuttinant, K.; Manosroi, W.; Biot, C.; Akazawa, H.; Akihisa, T.; Issarangporn, W.; Manosroi, A. Novel frrocenic steroidal drug derivatives and their bioactivities. J. Med. Chem., 2010, 53(10), 3937-3943.
Knauer, S.; Biersack, B.; Zoldakova, M.; Effenberger, K.; Milius, W.; Schobert, R. Melanoma-specific ferrocene esters of the fungal cytotoxin illudin M. Anti-Cancer Drugs, 2009, 20(8), 676-681.
Long, B.; Liang, S.; Xin, D.; Yang, Y.; Xiang, J. Synthesis, characterization and in vitro antiproliferative activities of new 13-cis-retinoyl ferrocene derivatives. Eur. J. Med. Chem., 2009, 44(6), 2572-2576.
Ong, C-W.; Jeng, J-Y.; Juang, S-S.; Chen, C-F. A ferrocene-intercalator conjugate with a potent cytotoxicity. Bioorg. Med. Chem. Lett., 1992, 2(9), 929-932.
(a)Kowalski, K.; Koceva-Chyła, A.; Pieniążek, A.; Bernasińska, J.; Skiba, J.; Rybarczyk-Pirek, A.J.; Jóźwiak, Z. The synthesis, structure, electrochemistry and in vitro anticancer activity studies of ferrocenyl-thymine conjugates. J. Organomet. Chem., 2012, 700, 58-68.
(b)Skiba, J.; Karpowicz, R.; Szabó, I.; Therrien, B.; Kowalski, K. Synthesis and anticancer activity studies of ferrocenyl-thymine-3,6-dihydro-2H-thiopyranes – A new class of metallocene-nucleobase derivatives. J. Organomet. Chem., 2015, 794, 216-222.
Tan, Q.; Zhang, Z.; Hui, J.; Zhao, Y.; Zhu, L. Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors. Bioorg. Med. Chem., 2014, 22(1), 358-365.
Amr, A.E.; Mohamed, A.M.; Mohamed, S.F.; Abdel-Hafez, N.A.; Hammam, A.G. Anticancer activities of some newly synthesized pyridine, pyrane, and pyrimidine derivatives. Bioorg. Med. Chem., 2006, 14(16), 5481-5488.
Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; Arafa, R.K.; El-Hossary, E.M. In vitro anticancer screening and radiosensitizing evaluation of some new quinolines and pyrimido[4,5-b]quinolines bearing a sulfonamide moiety. Eur. J. Med. Chem., 2010, 45(9), 3677-3684.
Skiba, J.; Kowalski, K.; Prochnicka, A.; Ott, I.; Solecka, J.; Rajnisz, A.; Therrien, B. Metallocene-uracil conjugates: Synthesis and biological evaluation of novel mono-, di- and tri-nuclear systems. J. Organomet. Chem., 2015, 782, 52-61.
Kowalski, K.; Koceva-Chyła, A.; Pieniążek, K.; Bernasińska, J.; Skiba, J.; Rybarczyk-Pirek, A.J.; Jóźwiak, Z. The synthesis, structure, electrochemistry and in vitro anticancer activity studies of ferrocenyl-thymine conjugates. J. Organomet. Chem., 2009, 694, 1041-1048.
Simenel, A.A.; Morozova, E.A.; Snegur, L.V.; Zykova, S.I.; Kachala, V.V.; Ostrovskaya, L.A.; Bluchterova, N.V.; Fomina, M.M. Simple route to ferrocenyl alkyl nucleobases. Antitumor activity in vivo. Appl. Organomet. Chem., 2009, 23, 219-224.
Efremova, A.S.; Shram, S.I.; Drenichev, M.S.; Posypanova, G.A.; Myasoedov, N.F.; Mihaylov, S.N. The selective toxic effect of dialdehyde derivatives of the pyrimidine nucleosides on human tumor cells. Biochem. Moscow Suppl. Ser. B, 2014, 8, 318-322.
Guo, Y.; Wang, S-Q.; Ding, Z-Q.; Zhou, J.; Ruan, B-F. Synthesis, characterization and antitumor activity of novel ferrocene bisamide derivatives containing pyrimidine-moiety. J. Organomet. Chem., 2017, 851, 150-159.
Sonn, A.; Litten, W. Über den γ-Phenylacetessigester. Chem. Ber., 1933, 66(10), 1512-1520.
Anderson, G.W.; Halverstadt, I.F.; Miller, W.H.; Roblin, Jr , R.O. Studies in hemotherapy. X. Antithyroid compounds. Synthesis of 5- and 6-substituted 2-thiouracils from β-Oxoesters and Thiourea. J. Am. Chem. Soc., 1945, 67(12), 2197-2200.
Clark, J.; Munawar, Z. Heterocyclic Studies. Part XIX. Some 6-(Substituted pheny1)-uracil and -thiouracil Derivatives. J. Chem. Soc. C, 1971, 1945-1948.
Ping, L.; Yu, Y-H.; Chen, Z-J.; Hou, G-F.; Chen, Y-M.; Maa, D-S.; Gao, J-S.; Gong, X-F. Syntheses, structures, catalytic and antitumor activities of a series of pyrimidine derivatives coordination complexes. Synth. Met., 2015, 203, 164-173.
Galow, T.H.; Ilhan, F.; Cooke, G.; Rotello, V.M. Recognition and Encapsulation of an Electroactive Guest within a Dynamically Folded Polymer. J. Am. Chem. Soc., 2000, 122(15), 3595-3598.
Zhao, Y.; Truhlar, D.G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Account., 2008, 120(1-3), 215-241.
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Son-nenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A., Jr; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Nor-mand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Re-ga, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, Ö.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2009.
Feller, D. The role of databases in support of computational chemistry calculations. J. Comp. Chem., 1996, 17(13), 1571-1586.
Schuchardt, K.L.; Didier, B.T.; Elsethagen, T.; Sun, L.; Gurumoorthi, V.; Chase, J.; Li, J.; Windus, T.L. Basis set exchange: a community database for computational sciences. J. Chem. Inf. Model., 2007, 47(3), 1045-1052.
Rappoport, D.; Furche, F. Property-optimized Gaussian basis sets for molecular response calculations. J. Chem. Phys., 2010, 133(13), 134105-134111.
McLean, A.D.; Chandler, G.S. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z=11–18. J. Chem. Phys., 1980, 72, 5639.
Bär, R.; Heinis, T.; Nager, C.; Jungen, M. Photoionization of ferrocene. Chem. Phys. Lett., 1982, 91(6), 440-442.
Mather, J.P.; Roberts, P.E. Introduction to cell and tissue culture. Theory and technique; Plenum Press: New York, 1998.

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Year: 2019
Published on: 13 November, 2018
Page: [160 - 164]
Pages: 5
DOI: 10.2174/1570179415666181113143516
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