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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) 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.

SUBMITTER: Lopez-Ramos M

PROVIDER: S-EPMC5374095 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

López-Ramos Maria M Figueroa-Valverde Lauro L Herrera-Meza Socorro S Rosas-Nexticapa Marcela M Díaz-Cedillo Francisco F García-Cervera Elodia E Pool-Gómez Eduardo E Cahuich-Carrillo Regina R

Journal of chemical biology 20170223 2

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 a ...[more]

PMID: 28405241

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Project description:Mostotrin (MT), a novel compound, at least five orders of magnitude more soluble in water than its mother substance, was designed and synthesised from tryptanthrin (TR). Its structure was established by nuclear magnetic resonance and mass spectrometry data and confirmed by X‑ray analysis, revealing that MT is a pentacyclic product with an additional pseudo‑cycle formed with the participation of one intramolecular hydrogen bond. Antimicrobial activity and cytotoxic action against tumour cells in vitro, as well as anti‑tumour effects, acute toxicity and anti‑inflammatory activities in vivo, were evaluated. Antimicrobial properties of MT against Mycobacterium spp and Bacillus cereus ATCC 10702 appeared to be the same as that of TR, but against the other strains used it was weaker. Furthermore, MT exhibited 5‑10 times higher cytotoxic activities against tumour cell lines HCT‑116, МСF‑7 and K‑562 than TR, but was less toxic than TR (LD50 of MT was 375 mg/kg, while LD50 for TR was 75 mg/kg). Additionally, compounds MT and TR were studied in DNA binding tests. The quenching of its fluorescence on addition to DNA solution established MT to be capable of binding to DNA. Its anti‑tumour action in vivo on mice with the ascitic form of Ehrlich carcinoma was promising, particularly with joint application of MT and the antitumour drug doxorubicin. In this model, the survival and life span for the doxorubicin and 1 co‑treatment group were significantly higher compared to doxorubicin treatment alone. The compound MT showed a lower immunosuppressive effect than TR at the early stages of inflammation induced in mice by LPS from E. сoli (MT hardly inhibited the release of IL‑1, IL‑2, or INF‑γ). These results demonstrated that MT is a perspective hit compound for drug development. In our opinion, further evaluation on the biological effects of MT and its synthetic analogues could lead to safer and more effective anti‑tumour and anti‑tuberculosis agents than TR itself. MT has also the prospect of application in combination with known anti‑tumour drugs for the treatment of oncological diseases.

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

Publications

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

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