Synthesis and In Vitro Antitumor Effect of New Vindoline-steroid Hybrids

Author(s): András Keglevich, Vivian Zsiros, Péter Keglevich*, Áron Szigetvári, Miklós Dékány, Csaba Szántay, Erzsébet Mernyák, János Wölfling, László Hazai*.

Journal Name: Current Organic Chemistry

Volume 23 , Issue 8 , 2019

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Abstract:

10-Aminovindoline and 17-desacetylvindoline were coupled with 5α- dihydrotestosterone hemisuccinate and 19-nortestosterone hemisuccinate. As a result, four vindoline-steroid hybrids were synthesized via a succinate linker. One of the new hybrid compounds showed significant anticancer effect in vitro in the case of colon cancer and melanoma cell lines.

Keywords: Vinca alkaloids, vindoline, steroid, succinate linker, hybrid molecules, antitumor activity.

[1]
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.
[2]
Decker, M. Design of Hybrid Molecules for Drug Development, 1st ed; Elsevier Ltd.: Oxford, 2017.
[3]
Mishra, S.; Singh, P. Hybrid molecules: the privileged scaffolds for various pharmaceuticals. Eur. J. Med. Chem., 2016, 124, 500-536.
[4]
Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res., 2008, 41(1), 69-77.
[5]
Decker, M. Hybrid molecules incorporating natural products: applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem., 2011, 18(10), 1464-1475.
[6]
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, 194, 1-4.
[http://dx.doi.org/10.1080/10426507.2018.1550780]
[7]
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.
[8]
Szabó, J.; Jerkovics, N.; Schneider, G.; Wölfling, J.; Bózsity, N.; Minorics, R.; Zupkó, I.; Mernyák, E. Synthesis and in vitro antiproliferative evaluation of C-13 epimers of triazolyl-d-secoestrone alcohols: the first potent 13α-d-secoestrone derivative. Molecules, 2016, 21(5), 611-623.
[9]
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.
[10]
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.
[11]
Keglevich, P.; Hazai, L.; Gorka-Kereskényi, Á.; Péter, L.; Gyenese, J.; Lengyel, Zs.; Kalaus, Gy.; Dubrovay, Zs.; Dékány, M.; Orbán, E.; Szabó, I.; Bánóczi, Z.; Szántay, Cs., Jr; Szántay, Cs. Synthesis and in vitro antitumor effect of new vindoline derivatives coupled with amino acid esters. Heterocycles, 2013, 87(11), 2299-2317.
[12]
Bánóczi, Z.; Keglevich, A.; Szabó, I.; Ranđelović, I.; Hegedüs, Z.; Regenbach, F.L.; Keglevich, P.; Lengyel, Zs.; Gorka-Kereskényi, Á.; Dubrovay, Zs.; Háda, V.; Szántay, Cs., 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
[13]
Keglevich, P.; Szántay, Cs.; Hazai, L. The chemistry of galanthamine. classical synthetic methods and comprehensive study on its analogues. Mini Rev. Med. Chem., 2016, 16(18), 1450-1461.
[14]
Ngo, Q.A.; Roussi, F.; Thoret, S.; Guéritte, F. Elaboration of simplified vinca alkaloids and phomopsin hybrids. Chem. Biol. Drug Des., 2010, 75(3), 284-294.
[15]
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. 1-76.
[16]
Son, J.K.; Rosazza, J.P.N.; Duffel, M.W. Vinblastine and vincristine are inhibitors of monoamine oxidase B. J. Med. Chem., 1990, 33(7), 1845-1848.
[17]
Bölcskei, H.; Szabó, L.; Szántay, Cs. Synthesis of vinblastine derivatives. Frontiers Nat. Prod. Chem, 2005, 1, 43-49.
[18]
Keglevich, P.; Hazai, L.; Kalaus, Gy.; Szántay, Cs. Modifications on the Basic skeletons of vinblastine and vincristine. Molecules, 2012, 17(5), 5893-5914.
[19]
Shi, Q.; Chen, K.; Morris-Natschke, S.L.; Lee, K.S. Recent progress in the development of tubulin inhibitors as antimitotic antitumor agents. Curr. Pharm. Des., 1998, 4(3), 219-248.
[20]
Iwasaki, S. Antimitotic agents: chemistry and recognition of tubulin molecule. Med. Res. Rev., 1993, 13(2), 183-198.
[21]
Segaloff, A.; Horwitt, B.N.; Carabasi, R.A.; Murison, P.J.; Schlosser, J.V. Hormonal therapy in cancer of the breast. X. The effect of vinyltestosterone therapy on clinical course and hormonal excretion. Cancer, 1955, 8(5), 82-86.
[22]
Llewellyn, W. Anabolics, 10th ed; Molecular Nutrition Llc: Jupiter, 2011, pp. 193-194, 402-412, 460-467.
[23]
Figueroa-Valverde, L.; Díaz-cedillo, F.; Camacho-Luis, A.; López, R.M.; Elodia, G.C. An efficient Synthesis of amino-dihydrotestosterone derivative. Int. J. Chemtech Res., 2010, 2(1), 557-561.
[24]
Jiang, J.; Zhang, H.; Li, G.; Wang, Z.; Wang, J.; Zhao, H. Preparation of Anti-nortestosterone antibodies and development of an indirect heterologous competitive enzyme-linked immunosorbent assay to detect nortestosterone residues in animal urine. Anal. Lett., 2011, 44(14), 2373-2393.
[25]
Gorka-Kereskényi, Á.; Szabó, L.; Hazai, L.; Lengyel, M.; Szántay, Cs., Jr; Sánta, Zs.; Kalaus, Gy.; Szántay, Cs. Aromatic electrophilic substitutions on vindoline. Heterocycles, 2007, 71(7), 1553-1563.
[26]
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.
[27]
National Institutes of Health, National Cancer Institute, Division of Cancer Treatment & Diagnosis, Developmental Therapeutics Program. https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm https://dtp.cancer.gov/databases_tools/docs/compare/compare_methodology.htm
[28]
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.J. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Nat. Cancer Inst, 1991, 83(11), 757-766.
[29]
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.
[30]
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.


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Article Details

VOLUME: 23
ISSUE: 8
Year: 2019
Page: [959 - 967]
Pages: 9
DOI: 10.2174/1385272823666190614113218

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