Abstract
An important approach to the development of new antitumor agents is the synthesis of conjugates containing two or more structural units. Taking this into consideration, vindoline derivatives were coupled with triphenylphosphine, to afford the expected phosphonium salts. The new hybrid entities were characterized by NMR spectroscopy, and their anticancer activity was also evaluated.
Keywords: Anticancer drugs, dimer Vinca alkaloids, vindoline, triphenylphosphine, phosphonium salts, antiproliferative activity.
Graphical Abstract
[1]
Blasko, G.; Cordell, G.A. Isolation, Structure Elucidation, and Biosynthesis of The Bisindole Alkaloids of Catharanthus. In:The Alkaloids; Brossi, A.; Suffness, M., Eds.; Academic Press: New York, 1990, Vol. 37, pp. 1-240.
[3]
Ehrhardt, H.; Pannert, L.; Pfeiffer, S.; Wachter, F.; Amtmann, E.; Jeremias, I. Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies. Br. J. Pharmacol., 2013, 168(7), 1558-1569.
[4]
Mukhtar, E.; Adhami, V.M.; Mukhtar, H. Targeting microtubules by natural agents for cancer therapy. Mol. Cancer Ther., 2014, 13(2), 275-284.
[5]
Wang, Y.; Benz, F.W.; Wu, Y.; Wang, Q.; Chen, Y.; Chen, X.; Li, H.; Zhang, Y.; Zhang, R.; Yang, J. Structural insights into the pharmacophore of vinca domain inhibitors of microtubules. Mol. Pharmacol., 2016, 89(2), 233-242. [http://dx.doi.org/10.1124/mol.115.100149]. [PMID: 26660762].
[6]
Moudi, M.; Go, R.; Yien, C.Y.; Nazre, M. Vinca alkaloids. Int. J. Prev. Med., 2013, 4(11), 1231-1235.
[7]
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer, 2004, 4(4), 253-265.
[8]
Keglevich, P.; Hazai, L.; Dubrovay, Zs.; Sánta, Zs.; Dékány, M.; Szántay, Cs., Jr; Kalaus, Gy.; Szántay, Cs. Bisindole alkaloids condensed with a cyclopropane ring, part 2. cyclopropano-vinorelbine and its derivatives. Heterocycles, 2015, 90(1), 316-326.
[9]
Hu, L.; Song, W.; Meng, Y.; Guo, D.; Liu, X.; Hu, L. Synthesis and structure-activity relationship studies of cytotoxic vinorelbine amide analogues. Bioorg. Med. Chem. Lett., 2012, 22(24), 7547-7550.
[10]
Keglevich, A.; Mayer, S.; Pápai, R.; Szigetvári, Á.; Sánta, Z.; Dékány, M.; Szántay, C., Jr; Keglevich, P.; Hazai, L. Attempted synthesis of vinca alkaloids condensed with three-membered rings. Molecules, 2018, 23(10), 2574-2594.
[11]
Keglevich, P.; Hazai, L.; Kalaus, G.; Szántay, C. Modifications on the basic skeletons of vinblastine and vincristine. Molecules, 2012, 17(5), 5893-5914.
[12]
Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P.M.S.; Dhar, K.L. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids. Eur. J. Med. Chem., 2014, 77, 422-487.
[13]
Decker, M. Design of Hybrid Molecules for Drug Development, 1st ed; Elsevier Ltd.: Oxford, 2017.
[14]
Choudhary, S.; Singh, P.K.; Verma, H.; Singh, H.; Silakari, O. Success stories of natural product-based hybrid molecules for multi-factorial diseases. Eur. J. Med. Chem., 2018, 151, 62-97.
[15]
Shaveta.; Mishra, S.; Singh, P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. Eur. J. Med. Chem., 2016, 124, 500-536.
[16]
Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem., 2011, 18(10), 1464-1475.
[17]
Meunier, B. Hybrid molecules with a dual mode of action: Dream or reality? Acc. Chem. Res., 2008, 41(1), 69-77.
[18]
Kant, R.; Kumar, D.; Agarwal, D.; Gupta, R.D.; Tilak, R.; Awasthi, S.K.; Agarwal, A. Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities. Eur. J. Med. Chem., 2016, 113, 34-49.
[19]
Rodríguez-Hernández, D.; Demuner, A.J.; Barbosa, L.C.A.; Heller, L.; Csuk, R. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents. Eur. J. Med. Chem., 2016, 115, 257-267.
[20]
Keglevich, P.; Hazai, L.; Gorka-Kereskényi, Á.; Péter, L.; Gyenese, J.; Lengyel, Z.S.; Kalaus, G.Y.; Dubrovay, Z.S.; Dékány, M.; Orbán, E.; Szabó, I.; Bánóczi, Z.; Szántay, C.S., Jr; Szántay, C.S. Synthesis and in vitro antitumor effect of new vindoline derivatives coupled with amino acid esters. Heterocycles, 2013, 87(11), 2299-2317.
[21]
Bánóczi, Z.; Gorka-Kereskényi, Á.; Reményi, J.; Orbán, E.; Hazai, L.; Tökési, N.; Oláh, J.; Ovádi, J.; Béni, Z.; Háda, V.; Szántay, C., Jr; Hudecz, F.; Kalaus, G.; Szántay, C. Synthesis and in vitro antitumor effect of vinblastine derivative-oligoarginine conjugates. Bioconjug. Chem., 2010, 21(11), 1948-1955.
[22]
Bánóczi, Z.; Keglevich, A.; Szabó, I.; Ranđelović, I.; Hegedüs, Z.; Regenbach, F.L.; Keglevich, P.; Lengyel, Z.; Gorka-Kereskényi, Á.; Dubrovay, Z.; Háda, V.; Szigetvári, Á.; Szántay, C., Jr; Hazai, L.; Tóvári, J.; Hudecz, F. The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide. J. Pept. Sci., 2018, 24(10)e3118
[23]
Tsepaeva, O.V.; Nemtarev, A.V.; Abdullin, T.I.; Grigor’eva, L.R.; Kuznetsova, E.V.; Akhmadishina, R.A.; Ziganshina, L.E.; Cong, H.H.; Mironov, V.F. Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin. J. Nat. Prod., 2017, 80(8), 2232-2239.
[24]
Passarella, D.; Giardini, A.; Peretto, B.; Fontana, G.; Sacchetti, A.; Silvani, A.; Ronchi, C.; Cappelletti, G.; Cartelli, D.; Borlak, J.; Danieli, B. Inhibitors of tubulin polymerization: Synthesis and biological evaluation of hybrids of vindoline, anhydrovinblastine and vinorelbine with thiocolchicine, podophyllotoxin and baccatin III. Bioorg. Med. Chem., 2008, 16(11), 6269-6285.
[25]
Keglevich, A.; Szigetvári, Á.; Dékány, M.; Szántay, Cs., Jr; Keglevich, P.; Hazai, L. Synthesis of vinca alkaloid–triphenylphosphine derivatives having potential antitumor effect. Phosph. Sulf. Sil. Rel. Elements, 2019, 1-4.
[26]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, 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(11), 757-766.
[27]
Alley, M.C.; Scudiero, D.A.; Monks, A.; Hursey, M.L.; Czerwinski, M.J.; Fine, D.L.; Abbott, B.J.; Mayo, J.G.; Shoemaker, R.H.; Boyd, M.R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 1988, 48(3), 589-601.
[28]
Shoemaker, R.H.; Monks, A.; Alley, M.C.; Scudiero, D.A.; Fine, D.L.; McLemore, T.L.; Abbott, B.J.; Paull, K.D.; Mayo, J.G.; Boyd, M.R. Development of human tumor cell line panels for use in disease-oriented drug screening. Prog. Clin. Biol. Res., 1988, 276, 265-286.
[29]
National Institutes of Health, National Cancer Institute, Division of Cancer
Treatment & Diagnosis, Developmental Therapeutics Program, 2018. Available
at: https://dtp.cancer.gov/discovery_development/nci-60/methodology.htmhttps://dtp.cancer.gov/databases_tools/docs/compare/compare_methodology.htm
[30]
NIH, National Cancer Institute, Division of Cancer Treatment & Diagnosis,
Developmental Therapeutics Program, 2018. Available at: https://dtp.cancer.gov/databases_tools/data_search.htm
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