title: Design and synthesis of a new steroid-macrocyclic derivative with biological activity.
abstract: The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound11) 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 (3and4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7and8), and (e) amido-steroid (9and10). Finally,11was prepared by removing thetert-butyldimethylsilane fragment of10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of11was 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 with11. 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.
authors.affiliation: Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico.
authors.forename: Maria
authors.initials: M
authors.lastname: López-Ramos
authors.affiliation: Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico.
authors.forename: Lauro
authors.initials: L
authors.lastname: Figueroa-Valverde
authors.affiliation: Instituto de Investigaciones Psicológicas, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n Col Industrial Animas, C.P. 91190 Xalapa, VER Mexico.
authors.forename: Socorro
authors.initials: S
authors.lastname: Herrera-Meza
authors.affiliation: Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, C.P. 91010 Xalapa, VER Mexico.
authors.forename: Marcela
authors.initials: M
authors.lastname: Rosas-Nexticapa
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala s/n Col, C.P. 11340 Santo Tomas, DF Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Díaz-Cedillo
authors.affiliation: Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico.
authors.forename: Elodia
authors.initials: E
authors.lastname: García-Cervera
authors.affiliation: Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pool-Gómez
authors.affiliation: Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico.
authors.forename: Regina
authors.initials: R
authors.lastname: Cahuich-Carrillo
keywords: Cycloheptadecaphane; Inotropic activity; Macrocyclic; Steroid; Testosterone