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Design and synthesis of a new steroid-macrocyclic derivative with biological activity

  • Original Article
  • Published:
Journal of Chemical Biology

Abstract

The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound 11) and characterize the molecular mechanism involved in its biological activity. The first step was achieved by synthesis of a macrocyclic derivative involving a series of reactions for the preparation of several steroid derivatives such as (a) steroid-pyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tert-butyldimethylsilane fragment of 10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of 11 was evaluated in presence of prazosin, metoprolol, indomethacin, nifedipine, and flutamide to characterize its molecular mechanism. Theoretical experiments were carried out with a Docking model, to assess potential interactions of androgen receptor with 11. The results showed that only this macrocyclic derivative exerts changes on perfusion pressure and vascular resistance translated as the positive inotropic effect, and this effect was blocked with flutamide; these data indicate that the positive inotropic activity induced by this macrocyclic derivative was via androgen receptor activation. The theoretical results indicated that the interaction of the macrocyclic derivative with the androgen receptor involves several amino acid residues such as Leu704, Asn705, Met780, Cys784, Met749, Leu762, Phe764, Ser778, and Met787. In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

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Notes

  1. Physiologic saline solution (Krebs-Henseleit solution; it was actively bubbled with a mixture of O2/CO2 (95:5/5%) and regulated at a pH of 7.4 and 37 °C) was composed of NaCl, 117.8 mmol; KCl, 6 mmol; CaCl2, 1.75 mmol; NaH2PO4, 1.2 mmol; MgSO4, 1.2 mmol; NaHCO3, 24.2 mmol; glucose, 5 mmol; and sodium pyruvate 5 mmol, and the coronary flow was adjusted with a variable speed peristaltic pump.

    Krebs-Henseleit solution was actively bubbled with a mixture of O2/CO2 (95:5/5 %) and regulated at a pH of 7.4 and 37°C.

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Authors and Affiliations

  1. Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039, Campeche, Mexico

    Maria López-Ramos, Lauro Figueroa-Valverde, Elodia García-Cervera, Eduardo Pool-Gómez & Regina Cahuich-Carrillo

  2. Instituto de Investigaciones Psicológicas, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n Col Industrial Animas, C.P. 91190, Xalapa, VER, Mexico

    Socorro Herrera-Meza

  3. Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, C.P. 91010, Xalapa, VER, Mexico

    Marcela Rosas-Nexticapa

  4. Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala s/n Col, C.P. 11340, Santo Tomas, DF, Mexico

    Francisco Díaz-Cedillo

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  1. Maria López-Ramos
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  2. Lauro Figueroa-Valverde
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  6. Elodia García-Cervera
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  7. Eduardo Pool-Gómez
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  8. Regina Cahuich-Carrillo
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Corresponding author

Correspondence to Lauro Figueroa-Valverde.

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The experimental methods used in this investigation were reviewed and approved by the Animal Care and Use Committee of University Autonomous of Campeche (no. PI-420/12) and were in accordance with the guide for the care and use of laboratory animals [10]. Male Wistar rats, weighing 200–250 g, were obtained from University Autonomous of Campeche.

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López-Ramos, M., Figueroa-Valverde, L., Herrera-Meza, S. et al. Design and synthesis of a new steroid-macrocyclic derivative with biological activity. J Chem Biol 10, 69–84 (2017). https://doi.org/10.1007/s12154-017-0165-0

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  • DOI: https://doi.org/10.1007/s12154-017-0165-0

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