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

Journal of chemical biology

article

Maria López-Ramos¹  Lauro Figueroa-Valverde¹  Socorro Herrera-Meza²  Marcela Rosas-Nexticapa²  Francisco Díaz-Cedillo³  Elodia García-Cervera¹  Eduardo Pool-Gómez¹  Regina Cahuich-Carrillo¹ 

[1] Laboratory of Pharmacochemistry, University Autonomous of Campeche;Instituto de Investigaciones Psicológicas, Universidad Veracruzana;Instituto Politécnico Nacional

关键词: Testosterone;    Cycloheptadecaphane;    Inotropic activity;    Steroid;    Macrocyclic;   

DOI  :  10.1007/s12154-017-0165-0

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

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 Leu 704 , Asn 705 , Met 780 , Cys 784 , Met 749 , Leu 762 , Phe 764 , Ser 778 , and Met 787 . In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

【 授权许可】

CC BY