New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties

Carlos Bustos, Elies Molins, Juan Guillermo Cárcamo, Marcelo N. Aguilar, Christian Sánchez, Ignacio Moreno-Villoslada, Hiroyuki Nishide, Angela Mesías-Salazar, Ximena Zarate, Eduardo Schott

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Synthesis of (E)-3,5-dimethyl-4-(R-phenyldiazenyl)isoxazoles was carried out by reacting β-diketohydrazones (R-C<inf>6</inf>H<inf>4</inf>-NHNC(COCH<inf>3</inf>)<inf>2</inf>) with hydroxylammonium chloride, where R = 4-N(CH<inf>3</inf>)<inf>2</inf>(1), 4-OH(2), 4-CH<inf>3</inf>(3), 4-OCH<inf>3</inf>(4), 4-H(5), 4-Cl(6) 4-Br(7), 4-CO<inf>2</inf>H(8), 4-CO<inf>2</inf>CH<inf>2</inf>CH<inf>3</inf>(9), 4-COCH<inf>3</inf>(10), 4-CN(11), 4-NO<inf>2</inf>(12), 4-CH<inf>2</inf>CO<inf>2</inf>CH<inf>2</inf>CH<inf>3</inf>(13), 3-Cl(14), 2-OH(15), 2-Cl(16), 2-NO<inf>2</inf>(17), 2-CO<inf>2</inf>H(18). All compounds were characterized by EA and spectroscopic methods. The crystalline structure of two of the compounds, (7) and (17), were solved by the X-ray diffraction method. DFT and TDDFT computations were performed in order to characterize the molecular geometry and the molecular orbitals involved in the transitions. Besides, a biological activity study was performed to evaluate the toxicity of the compounds towards human promyelocytic leukemia cell line, HL-60, using the MTT reduction method. The IC<inf>50</inf> values are in a wide concentration range, 86-755 μM. Isoxazoles (3) and (6) were the most cytotoxic. Expression analysis in HL-60 cells was carried out with compounds (3) and (6) by RT-PCR, in order to determine the effect on the expression levels of mRNA that codify for the genes Bcl-2, Bax and p21<sup>WAF-1</sup>. Isoxazole (3) induced a decrease in the expression of Bcl-2, whereas isoxazole (6) showed an opposite behaviour. However, these isoxazoles had no effect on mRNA levels of Bax. On the other hand, both isoxazoles increased the levels of p21<sup>WAF-1</sup>. These results suggest that the cytotoxic activity of isoxazole (3) would be the sum of effects triggered by promotion of apoptosis and cell cycle arrest, whereas for isoxazole (6) it would be mainly through cell cycle arrest.

    Original languageEnglish
    Pages (from-to)4295-4307
    Number of pages13
    JournalNew Journal of Chemistry
    Volume39
    Issue number6
    DOIs
    Publication statusPublished - 2015 Jun 1

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    Isoxazoles
    Cells
    Derivatives
    Molecular orbitals
    Cell death
    Bioactivity
    Discrete Fourier transforms
    Toxicity
    Genes
    Crystalline materials
    X ray diffraction
    Geometry
    Messenger RNA
    Hydroxylamine
    Apoptosis

    ASJC Scopus subject areas

    • Chemistry(all)
    • Catalysis
    • Materials Chemistry

    Cite this

    Bustos, C., Molins, E., Cárcamo, J. G., Aguilar, M. N., Sánchez, C., Moreno-Villoslada, I., ... Schott, E. (2015). New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties. New Journal of Chemistry, 39(6), 4295-4307. https://doi.org/10.1039/c4nj02427c

    New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties. / Bustos, Carlos; Molins, Elies; Cárcamo, Juan Guillermo; Aguilar, Marcelo N.; Sánchez, Christian; Moreno-Villoslada, Ignacio; Nishide, Hiroyuki; Mesías-Salazar, Angela; Zarate, Ximena; Schott, Eduardo.

    In: New Journal of Chemistry, Vol. 39, No. 6, 01.06.2015, p. 4295-4307.

    Research output: Contribution to journalArticle

    Bustos, C, Molins, E, Cárcamo, JG, Aguilar, MN, Sánchez, C, Moreno-Villoslada, I, Nishide, H, Mesías-Salazar, A, Zarate, X & Schott, E 2015, 'New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties', New Journal of Chemistry, vol. 39, no. 6, pp. 4295-4307. https://doi.org/10.1039/c4nj02427c
    Bustos C, Molins E, Cárcamo JG, Aguilar MN, Sánchez C, Moreno-Villoslada I et al. New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties. New Journal of Chemistry. 2015 Jun 1;39(6):4295-4307. https://doi.org/10.1039/c4nj02427c
    Bustos, Carlos ; Molins, Elies ; Cárcamo, Juan Guillermo ; Aguilar, Marcelo N. ; Sánchez, Christian ; Moreno-Villoslada, Ignacio ; Nishide, Hiroyuki ; Mesías-Salazar, Angela ; Zarate, Ximena ; Schott, Eduardo. / New 3,4,5-trisubstituted isoxazole derivatives with potential biological properties. In: New Journal of Chemistry. 2015 ; Vol. 39, No. 6. pp. 4295-4307.
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    abstract = "Synthesis of (E)-3,5-dimethyl-4-(R-phenyldiazenyl)isoxazoles was carried out by reacting β-diketohydrazones (R-C6H4-NHNC(COCH3)2) with hydroxylammonium chloride, where R = 4-N(CH3)2(1), 4-OH(2), 4-CH3(3), 4-OCH3(4), 4-H(5), 4-Cl(6) 4-Br(7), 4-CO2H(8), 4-CO2CH2CH3(9), 4-COCH3(10), 4-CN(11), 4-NO2(12), 4-CH2CO2CH2CH3(13), 3-Cl(14), 2-OH(15), 2-Cl(16), 2-NO2(17), 2-CO2H(18). All compounds were characterized by EA and spectroscopic methods. The crystalline structure of two of the compounds, (7) and (17), were solved by the X-ray diffraction method. DFT and TDDFT computations were performed in order to characterize the molecular geometry and the molecular orbitals involved in the transitions. Besides, a biological activity study was performed to evaluate the toxicity of the compounds towards human promyelocytic leukemia cell line, HL-60, using the MTT reduction method. The IC50 values are in a wide concentration range, 86-755 μM. Isoxazoles (3) and (6) were the most cytotoxic. Expression analysis in HL-60 cells was carried out with compounds (3) and (6) by RT-PCR, in order to determine the effect on the expression levels of mRNA that codify for the genes Bcl-2, Bax and p21WAF-1. Isoxazole (3) induced a decrease in the expression of Bcl-2, whereas isoxazole (6) showed an opposite behaviour. However, these isoxazoles had no effect on mRNA levels of Bax. On the other hand, both isoxazoles increased the levels of p21WAF-1. These results suggest that the cytotoxic activity of isoxazole (3) would be the sum of effects triggered by promotion of apoptosis and cell cycle arrest, whereas for isoxazole (6) it would be mainly through cell cycle arrest.",
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    AU - Molins, Elies

    AU - Cárcamo, Juan Guillermo

    AU - Aguilar, Marcelo N.

    AU - Sánchez, Christian

    AU - Moreno-Villoslada, Ignacio

    AU - Nishide, Hiroyuki

    AU - Mesías-Salazar, Angela

    AU - Zarate, Ximena

    AU - Schott, Eduardo

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    N2 - Synthesis of (E)-3,5-dimethyl-4-(R-phenyldiazenyl)isoxazoles was carried out by reacting β-diketohydrazones (R-C6H4-NHNC(COCH3)2) with hydroxylammonium chloride, where R = 4-N(CH3)2(1), 4-OH(2), 4-CH3(3), 4-OCH3(4), 4-H(5), 4-Cl(6) 4-Br(7), 4-CO2H(8), 4-CO2CH2CH3(9), 4-COCH3(10), 4-CN(11), 4-NO2(12), 4-CH2CO2CH2CH3(13), 3-Cl(14), 2-OH(15), 2-Cl(16), 2-NO2(17), 2-CO2H(18). All compounds were characterized by EA and spectroscopic methods. The crystalline structure of two of the compounds, (7) and (17), were solved by the X-ray diffraction method. DFT and TDDFT computations were performed in order to characterize the molecular geometry and the molecular orbitals involved in the transitions. Besides, a biological activity study was performed to evaluate the toxicity of the compounds towards human promyelocytic leukemia cell line, HL-60, using the MTT reduction method. The IC50 values are in a wide concentration range, 86-755 μM. Isoxazoles (3) and (6) were the most cytotoxic. Expression analysis in HL-60 cells was carried out with compounds (3) and (6) by RT-PCR, in order to determine the effect on the expression levels of mRNA that codify for the genes Bcl-2, Bax and p21WAF-1. Isoxazole (3) induced a decrease in the expression of Bcl-2, whereas isoxazole (6) showed an opposite behaviour. However, these isoxazoles had no effect on mRNA levels of Bax. On the other hand, both isoxazoles increased the levels of p21WAF-1. These results suggest that the cytotoxic activity of isoxazole (3) would be the sum of effects triggered by promotion of apoptosis and cell cycle arrest, whereas for isoxazole (6) it would be mainly through cell cycle arrest.

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