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 (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 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.

Evaluation of Biological Activity Exerted by Dibenzo[b,e]Thiophene-11(6H)-One on Left Ventricular Pressure Using an Isolated Rat Heart Model

“…The results showed that only compound 4 (Dibenzo[b,e]thiophene-11(6H)-one) significantly increases perfusion pressure in a time-dependent manner compared to compounds 1-3, 5-10 and the control conditions. These data suggest that Dibenzo[b,e]thiophene-11(6H)-one could produce changes in the coronary resistance such happening with other type of compounds [32,33]. Based on these data, in this study the biological activity produced by Dibenzo[b,e]thiophene-11(6H)-one on coronary resistance was evaluated.…”

Activity Exerted by Fluoro-2,4-Dioxaspiro[Bicyclo[3.3.1]Indene Derivative Against Ischemia/Reperfusion Injury

“…In this study, experimental protocols were reviewed and approved by the Animal care and use committee of University Autonomous of Campeche (UAC) and were in accordance with the guide for the care and use of laboratory animals [15].…”

Synthesis and theoretical activity evaluation of a new steroid-oxazolone derivative against COX1-1 and COX-2

“…The second stage was achieved by the synthesis of an ether-steroid derivative (3); it is important to mention that some reports have been reported for the preparation of ether derivatives via displacement of nitro group using methoxide as dipolar aprotic solvent [21,22]. In this study, 3 was prepared using a previously method reported [23]; the reaction was carried out through intramolecular displacement from nitro group by the hydroxyl group of the compound 2 in presence of DMSO/K 2 CO 3 (Figure 1). The 1 HNMR showed several signals for 3 at 0.90 ppm for methyl group bound to steroid nucleus; at 1.18 ppm for methyl bound to oxazole ring; at 1.22-3.10 and 6.43-6.54 ppm for steroid moiety; at 6.24 ppm for oxazole ring; at 7.72 for both hydroxyl and amine groups.…”