NOVEL LIGANDS OF HUMAN CYP7 ENZYMES – POSSIBLE MODULATORS OF CHOLESTEROL BLOOD LEVEL: COMPUTER SIMULATION STUDIES

Our in vitro studies showed that a couple of perspective steroidal derivatives showed previously biomedical potential via enzyme inhibition, receptor binding or antiproliferative effect against the cancer cells of reproductive tissues are able to bind to human CYP7 enzymes – key enzymes taking part in hydroxylation of cholesterol, 25-, 27-hydroxycholesterol and a number of steroidal hormones. In silico screening of binding affinity of the modified steroids toward CYP7 enzymes showed that interaction energy for the new ligands is comparable with consequent values, calculated for the ‘essential’ substrates of the enzymes – cholestenone (CYP7A1) and DHEA (CYP7B1). However, no correlation between binding energy and the affinity of the ligand was found. Novel ligands interact with conserved amino acids taking part in stabilization of natural substrates of CYP7 enzymes. A couple of structural features, governing ligand binding, were identified. Among which are planar structure of A-ring for CYP7A1 ligands, absence of many polar fragments in side-chain and presence of polar group at C3 position. Analysis of the docking results showed that CYP7B1 higher selectivity in comparison with CYP7A1 is connected by the structure of the cavity formed by α-helices I and B`. The data obtained will be used for the explanation of ligand specificity of human sterol- hydroxylases.

The Ugi-Smiles Reaction on Steroids: Discovery of Bioactive N,N-Disubstituted 3- Aminoestrones

The Ugi-Smiles multicomponent reaction is a powerful tool for obtaining <i>N-</i>arylamines from acidic phenols and has been widely used for gaining access to structurally diverse scaffolds. In this work we demonstrate that this isocyanide-based coupling can be used for the straightforward and efficient synthesis of <i>N,N-</i>disubstituted 3-aminoestrones, steroidal derivatives that usually show interesting biological activities. In this sense, we analyzed the scope and limitations of the reaction when applied to aromatic nitrosteroids and found that the outcome is highly influenced by the steric effects imposed by the steroidal skeleton. After optimization of the reaction conditions a set of thirteen N-substituted 3-aminoestromes were obtained, some of them with interesting antiproliferative and antiviral activities.

The Ugi-Smiles Reaction on Steroids: Discovery of Bioactive N,N-Disubstituted 3- Aminoestrones

The Ugi-Smiles multicomponent reaction is a powerful tool for obtaining <i>N-</i>arylamines from acidic phenols and has been widely used for gaining access to structurally diverse scaffolds. In this work we demonstrate that this isocyanide-based coupling can be used for the straightforward and efficient synthesis of <i>N,N-</i>disubstituted 3-aminoestrones, steroidal derivatives that usually show interesting biological activities. In this sense, we analyzed the scope and limitations of the reaction when applied to aromatic nitrosteroids and found that the outcome is highly influenced by the steric effects imposed by the steroidal skeleton. After optimization of the reaction conditions a set of thirteen N-substituted 3-aminoestromes were obtained, some of them with interesting antiproliferative and antiviral activities.

Heterocyclization of Thiophenes Derived from Estrone Followed by Cytotoxic, HTRF Kinase and Pim-1 Kinase Evaluations

Background: A wide range of heterocyclic steroidal derivatives gained a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the steroid nucleus are known in the market. Objective: Our main aim of this work was to synthesise a series of heterocyclic compounds especially thiophene and thienopyridine derivatives containing the estrone nucleus. The synthesized compounds posses antitumor and kinases inhibitions. Method: Thiophene derivatives of estrone were synthesized and used for further heterocyclization reactions through the reaction with the different reagent. Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. Conclusion: Compounds that showed high antiproliferative activity and c-Met- kinase inhibitions were tested for all compounds. The most promising compounds 3b, 5c, 6c, 8d, 8f, 13e, 13f, 18b and 20d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity where compounds 11c, 18b and 20f showed high activities. Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules.