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

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 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.