Design and synthesis of a new steroid-macrocyclic derivative with biological activity
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ORIGINAL ARTICLE
Design and synthesis of a new steroid-macrocyclic derivative with biological activity Maria López-Ramos 1 & Lauro Figueroa-Valverde 1 & Socorro Herrera-Meza 2 & Marcela Rosas-Nexticapa 3 & Francisco Díaz-Cedillo 4 & Elodia García-Cervera 1 & Eduardo Pool-Gómez 1 & Regina Cahuich-Carrillo 1
Received: 22 November 2016 / Accepted: 2 February 2017 / Published online: 23 February 2017 # Springer-Verlag Berlin Heidelberg 2017
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) steroidpyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroidimino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tertbutyldimethylsilane 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
* Lauro Figueroa-Valverde [email protected]
1
Laboratory of Pharmacochemistry, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche, Mexico
2
Instituto de Investigaciones Psicológicas, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n Col Industrial Animas, C.P. 91190 Xalapa, VER, Mexico
3
Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, C.P. 91010 Xalapa, VER, Mexico
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
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. Keywords Testosterone . Cycloheptadecaphane . Inotropic activity . Steroid . Macrocyclic
Introduction For several years, some macrocyclic derivatives have been developed in various fields of medicinal chemistry for the preparation of new drugs or for evaluation
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