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Abstract:

Over the last decades, much effort has been devoted to the design of the “ideal” library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged—in a minimalist way—by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Registro:

Documento: Artículo
Título:A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents
Autor:Alonso, F.; Quezada, M.J.; Gola, G.F.; Richmond, V.; Cabrera, G.M.; Barquero, A.A.; Ramírez, J.A.
Filiación:Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
CONICET – Universidad de Buenos Aires, Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Quimica Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
Palabras clave:antiproliferative agents; molecular complexity; multicomponent reactions; natural product mimics; phenanthrenes; antineoplastic agent; phenanthrenoid derivative; unclassified drug; antiproliferative activity; apoptosis; Article; cell survival; comparative study; cyclization; drug design; drug mechanism; drug screening; drug synthesis; electrospray mass spectrometry; HT-29 cell line; human; human cell; IC50; in vitro study; leukemia cell; molecular library; nonhuman; nuclear magnetic resonance spectroscopy; plant response; priority journal; protein conformation; proton nuclear magnetic resonance; structure activity relation
Año:2018
Volumen:13
Número:16
Página de inicio:1732
Página de fin:1740
DOI: http://dx.doi.org/10.1002/cmdc.201800295
Título revista:ChemMedChem
Título revista abreviado:ChemMedChem
ISSN:18607179
CODEN:CHEMG
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v13_n16_p1732_Alonso

Referencias:

  • Chen, H., Engkvist, O., Blomberg, N., Li, J., (2012) MedChemComm, 3, p. 312
  • Ramsay, R.R., Popovic-Nikolic, M.R., Nikolic, K., Uliassi, E., Bolognesi, M.L., (2018) Clin. Transl. Med., 7, p. 3
  • Sams-Dodd, F., (2013) Drug Discovery Today, 18, pp. 211-217
  • Sams-Dodd, F., (2005) Drug Discovery Today, 10, pp. 139-147
  • Hellerstein, M.K., (2008) Metab. Eng., 10, pp. 1-9
  • van Hattum, H., Waldmann, H., (2014) J. Am. Chem. Soc., 136, pp. 11853-11859
  • Bon, R.S., Waldmann, H., (2010) Acc. Chem. Res., 43, pp. 1103-1114
  • Opassi, G., Gesù, A., Massarotti, A., (2018) Drug Discovery Today, 23, pp. 565-574
  • Koch, M.A., Schuffenhauer, A., Scheck, M., Wetzel, S., Casaulta, M., Odermatt, A., Ertl, P., Waldmann, H., (2005) Proc. Natl. Acad. Sci. USA, 102, pp. 17272-17277
  • Leach, A.R., Hann, M.M., (2011) Curr. Opin. Chem. Biol., 15, pp. 489-496
  • Méndez-Lucio, O., Medina-Franco, J.L., (2017) Drug Discovery Today, 22, pp. 120-126
  • Lovering, F., Bikker, J., Humblet, C., (2009) J. Med. Chem., 52, pp. 6752-6756
  • Clemons, P.A., Bodycombe, N.E., Carrinski, H.A., Wilson, J.A., Shamji, A.F., Wagner, B.K., Koehler, A.N., Schreiber, S.L., (2010) Proc. Natl. Acad. Sci. USA, 107, pp. 18787-18792
  • Tajabadi, F.M., Campitelli, M.R., Quinn, R.J., (2013) Springer Sci. Rev., 1, pp. 141-151
  • Stotani, S., Lorenz, C., Winkler, M., Medda, F., Picazo, E., Ortega Martinez, R., Karawajczyk, A., Giordanetto, F., (2016) ACS Comb. Sci., 18, pp. 330-336
  • McLeod, M.C., Aubé, J., (2016) Tetrahedron, 72, pp. 3766-3774
  • Flagstad, T., Min, G., Bonnet, K., Morgentin, R., Roche, D., Clausen, M.H., Nielsen, T.E., (2016) Org. Biomol. Chem., 14, pp. 4943-4946
  • Feher, M., Schmidt, J.M., (2003) J. Chem. Inf. Comput. Sci., 43, pp. 218-227
  • Paciaroni, N.G., Ratnayake, R., Matthews, J.H., Norwood, V.M., Arnold, A.C., Dang, L.H., Luesch, H., Huigens, R.W., (2017) Chem. Eur. J., 23, pp. 4327-4335
  • Dömling, A., Wang, W., Wang, K., (2012) Chem. Rev., 112, pp. 3083-3135
  • Xiao, K., Zhang, H.J., Xuan, L.J., Zhang, J., Xu, Y.M., Bai, D.L., (2008) Stud. Nat. Prod. Chem., 34, pp. 453-646
  • Tóth, B., Hohmann, J., Vasas, A., (2018) J. Nat. Prod., 81, pp. 661-678
  • Sánchez-Duffhues, G., Calzado, M.A., de Vinuesa, A.G., Appendino, G., Fiebich, B.L., Loock, U., Lefarth-Risse, A., Muñoz, E., (2009) Biochem. Pharmacol., 77, pp. 1401-1409
  • Datla, P., Kalluri, M.D., Basha, K., Bellary, A., Kshirsagar, R., Kanekar, Y., Upadhyay, S., Rajagopal, V., (2010) Br. J. Pharmacol., 160, pp. 1158-1170
  • Kovács, A., Vasas, A., Hohmann, J., (2008) Phytochemistry, 69, pp. 1084-1110
  • López-Vallejo, F., Giulianotti, M.A., Houghten, R.A., Medina-Franco, J.L., (2012) Drug Discovery Today, 17, pp. 718-726
  • Boots, S.G., Johnson, W.S., (1966) J. Org. Chem., 31, pp. 1285-1287
  • Ulaczyk-Lesanko, A., Hall, D.G., (2005) Curr. Opin. Chem. Biol., 9, pp. 266-276
  • Wang, W., Ollio, S., Herdtweck, E., Dömling, A., (2011) J. Org. Chem., 76, pp. 637-644
  • Giovenzana, G.B., Tron, G.C., Di Paola, S., Menegotto, I.G., Pirali, T., (2006) Angew. Chem. Int. Ed., 45, pp. 1099-1102
  • (2006) Angew. Chem., 118, pp. 1117-1120
  • Sui, Q., Borchardt, D., Rabenstein, D.L., (2007) J. Am. Chem. Soc., 129, pp. 12042-12048
  • Sauer, W.H.B., Schwarz, M.K., (2003) J. Chem. Inf. Comput. Sci., 43, pp. 987-1003
  • Wirth, M., Sauer, W.H.B., (2011) Mol. Inform., 30, pp. 677-688
  • McLeod, M.C., Singh, G., Plampin, J.N., III, Rane, D., Wang, J.L., Day, V.W., Aubé, J., (2014) Nat. Chem., 6, pp. 133-140
  • Wenderski, T.A., Stratton, C.F., Bauer, R.A., Kopp, F., Tan, D.S., (2015) Methods Mol. Biol., 1263, pp. 225-242
  • Stratton, C.F., Newman, D.J., Tan, D.S., (2015) Bioorg. Med. Chem. Lett., 25, pp. 4802-4807
  • Swinney, D.C., Anthony, J., (2011) Nat. Rev. Drug Discovery, 10, pp. 507-519
  • Zheng, W., Thorne, N., McKew, J.C., (2013) Drug Discovery Today, 18, pp. 1067-1073
  • Muellner, M.K., Uras, I.Z., Gapp, B.V., Kerzendorfer, C., Smida, M., Lechtermann, H., Craig-Mueller, N., Nijman, S.M.B., (2011) Nat. Chem. Biol., 7, pp. 787-793
  • Chen, T., Ozel, D., Qiao, Y., Harbinski, F., Chen, L., Denoyelle, S., He, X., Aktas, B.H., (2011) Nat. Chem. Biol., 7, pp. 610-616
  • Alaimo, P.J., Shogren-Knaak, M.A., Shokat, K.M., (2001) Curr. Opin. Chem. Biol., 5, pp. 360-367
  • Kepp, O., Galluzzi, L., Lipinski, M., Yuan, J., Kroemer, G., (2011) Nat. Rev. Drug Discovery, 10, pp. 221-237
  • Franken, N.A.P., Rodermond, H.M., Stap, J., Haveman, J., van Bree, C., (2006) Nat. Protoc., 1, pp. 2315-2319
  • Kuo, C.-T., Hsu, M.-J., Chen, B.-C., Chen, C.-C., Teng, C.-M., Pan, S.-L., Lin, C.-H., (2008) Toxicol. Lett., 177, pp. 48-58
  • Song, J.I., Kang, Y.J., Yong, H.-Y., Chen, Y.C., Moon, A., (2011) Oncol. Rep., 27, pp. 813-818
  • D′Herde, K., Mussche, S., Roberg, K., (2003) Cell Proliferation and Apoptosis, pp. 209-240. , (Eds., D. Hughes, H. Mehmet, BIOS Scientific Publishers Ltd., Oxford
  • Polverino, A.J., Patterson, S.D., (1997) J. Biol. Chem., 272, pp. 7013-7021
  • Boehm, M., Zhang, L., Bodycombe, N., Maciejewski, M., Wassermann, A.M., (2016) Frontiers in Molecular Design and Chemical Information Science, pp. 345-364. , (Eds., R. J. Bienstock, V. Shanmugasundaram, J. Bajorath, American Chemical Society, Chapter 16
  • Rafferty, R.J., Hicklin, R.W., Maloof, K.A., Hergenrother, P.J., (2014) Angew. Chem. Int. Ed., 53, pp. 220-224
  • (2014) Angew. Chem., 126, pp. 224-228
  • Nilar, S.H., Ma, N.L., Keller, T.H., (2013) J. Comput. Aided. Mol. Des., 27, pp. 783-792
  • Lee, H.Y., Kumar, S., Lin, T.C., Liou, J.P., (2016) J. Nat. Prod., 79, pp. 1170-1173

Citas:

---------- APA ----------
Alonso, F., Quezada, M.J., Gola, G.F., Richmond, V., Cabrera, G.M., Barquero, A.A. & Ramírez, J.A. (2018) . A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents. ChemMedChem, 13(16), 1732-1740.
http://dx.doi.org/10.1002/cmdc.201800295
---------- CHICAGO ----------
Alonso, F., Quezada, M.J., Gola, G.F., Richmond, V., Cabrera, G.M., Barquero, A.A., et al. "A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents" . ChemMedChem 13, no. 16 (2018) : 1732-1740.
http://dx.doi.org/10.1002/cmdc.201800295
---------- MLA ----------
Alonso, F., Quezada, M.J., Gola, G.F., Richmond, V., Cabrera, G.M., Barquero, A.A., et al. "A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents" . ChemMedChem, vol. 13, no. 16, 2018, pp. 1732-1740.
http://dx.doi.org/10.1002/cmdc.201800295
---------- VANCOUVER ----------
Alonso, F., Quezada, M.J., Gola, G.F., Richmond, V., Cabrera, G.M., Barquero, A.A., et al. A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents. ChemMedChem. 2018;13(16):1732-1740.
http://dx.doi.org/10.1002/cmdc.201800295