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Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

ABSTRACT: 19-Nortestosterone C-17 epimers with prominent antiproliferative properties have been previously described. In our present study, five novel 17?-19-nortestosterones (3-7) were synthesized to increase their beneficial biological activities with no associated undesired hormonal effects. The compounds were screened by a viability assay against a panel of human adherent gynecological cancer cell lines. Three of the tested derivatives (3-5) exhibited a remarkable inhibitory effect on the proliferation of HeLa cells with IC50 values lower than that of our reference agent cisplatin (CIS). These three active agents also displayed considerable cancer selectivity as evidenced by their weaker growth inhibitory effect on non-cancerous fibroblast cells compared to CIS. The most potent newly synthesized 17?-chloro derivative (3) was selected for additional experiments in order to characterize its mechanism of action. Since nandrolone (19-nortestosterone, 1) is a structural analog with selective antiproliferative action on cervical carcinoma cells, it was utilized as a positive control in these studies. A lactate dehydrogenase (LDH) assay demonstrated a moderate cytotoxic effect of the test compounds. Cell cycle disturbance and the elevation of the hypodiploid population elicited by the test agents were detected by flow cytometry following propidium staining. The proapoptotic effects of the tested steroids were confirmed by fluorescent microscopy and a caspase-3 activity assay. Treatment-related caspase-9 activation without a substantial change in caspase-8 activity indicates the induction of the intrinsic apoptotic pathway. The selected agents directly influence the rate of tubulin assembly as evidenced by a polymerization assay. Yeast-based reporter gene assay revealed that the androgenic activity of the novel 19-nortestosterone derivative 3 is by multiple orders of magnitude weaker than that of the reference agent 1. Based on the behavior of the examined compounds it can be concluded that a halogen substitution of the 19-nortestosterone scaffold at the 17? position may produce compounds with unique biological activities. The results of the present study support that structurally modified steroids with negligible hormonal activity are a promising basis for the research and development of novel anticancer agents.

SUBMITTER: Gyovai A

PROVIDER: S-EPMC6072853 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

Gyovai András A Minorics Renáta R Kiss Anita A Mernyák Erzsébet E Schneider Gyula G Szekeres András A Kerekes Erika E Ocsovszki Imre I Zupkó István I

Frontiers in pharmacology 20180727

19-Nortestosterone C-17 epimers with prominent antiproliferative properties have been previously described. In our present study, five novel 17α-19-nortestosterones (3-7) were synthesized to increase their beneficial biological activities with no associated undesired hormonal effects. The compounds were screened by a viability assay against a panel of human adherent gynecological cancer cell lines. Three of the tested derivatives (3-5) exhibited a remarkable inhibitory effec ...[more]

PMID: 30100876

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Project description:A DFT study of the synthesized MAX phase Zr2SeC has been carried out for the first time to explore its physical properties for possible applications in many sectors. The studied properties are compared with prior known MAX phase Zr2SC. The structural parameters (lattice constants, volume, and atomic positions) are observed to be consistent with earlier results. The band structure and density of states (DOS) are used to explore the metallic conductivity, anisotropic electrical conductivity, and the dominant role of Zr-d states to the electrical conductivity at the Fermi level. Analysis of the peaks in the DOS and charge density mapping (CDM) of Zr2SeC and Zr2SC revealed the possible variation of the mechanical properties and hardness among them. The mechanical stability has been checked using elastic constants. The values of the elastic constants, elastic moduli and hardness parameters of Zr2SeC are found to be lowered than those of Zr2SC. The anisotropic behavior of the mechanical properties has been studied and analyzed. Technologically important thermodynamic properties such as the thermal expansion coefficient (TEC), Debye temperature (Θ D), entropy (S), heat capacity at constant volume (C v), Grüneisen parameter (γ) along with volume (V) and Gibbs free energy (G) are investigated as a function of both temperature (from 0 to 1600 K) and pressure (from 0 to 50 GPa). Besides, the Θ D, minimum thermal conductivity (K min), melting point (T m), and γ have also been calculated at room temperature and found to be lowered for Zr2SeC compared to Zr2SC owing to their close relationship with the mechanical parameters. The value of the Θ D, K min, T m, and TEC suggest Zr2SeC as a thermal barrier coating material. The optical properties such as dielectric constant (real and imaginary part), refractive index, extinction coefficient, absorption coefficient, photoconductivity, reflectivity, and loss function of Zr2SeC are computed and analyzed to reveal its possible applications.

Dataset Information

Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

Publications

Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

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