Andrea R. Nikolić
University of Novi Sad
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Featured researches published by Andrea R. Nikolić.
Bioorganic & Medicinal Chemistry | 2015
Andrea R. Nikolić; Edward T. Petri; Olivera R. Klisurić; Andjelka Ćelić; Dimitar Jakimov; Evgenija A. Djurendić; Katarina M. Penov Gaši; Marija N. Sakač
We report the synthesis of steroidal 16,17-seco-16,17a-dinitriles and investigate their antitumor cell properties. Compounds were evaluated for anticancer potential by in vitro antiproliferation studies, molecular docking and virtual screening. Several compounds inhibit the growth of breast and prostate cancer cell lines (MCF-7, MDA-MB-231 and PC3), and/or cervical cancer cells (HeLa). Supporting this, molecular docking predicts that steroidal 16,17-seco-16,17a-dinitriles could bind with high affinity to multiple molecular targets of breast and prostate cancer treatment (aromatase, estrogen receptor α, androgen receptor and 17α-hydroxylase) facilitated by D-seco flexibility and nitrile-mediated contacts. Thus, 16,17-seco-16,17a-dinitriles may be useful for the design of inhibitors of multiple steroidogenesis pathways. Strikingly, 10, a 1,4-dien-3-on derivative, displayed selective submicromolar antiproliferative activity against hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells (IC50 0.52, 0.11μM, respectively). Ligand-based 3D similarity searches suggest AKR1C, 17β-HSD and/or 3β-HSD subfamilies as responsible for this antiproliferative activity, while fast molecular docking identified AKR1C and ERβ as potential binders-both targets in the treatment of hormone-independent breast cancers.
MedChemComm | 2013
Katarina M. Penov-Gaši; Aleksandar M. Oklješa; Edward T. Petri; Andjelka Ćelić; Evgenija A. Djurendić; Olivera R. Klisurić; János Csanádi; Gyula Batta; Andrea R. Nikolić; Dimitar Jakimov; Marija N. Sakač
Here we report a convenient “click” synthesis for D-homo fused steroidal tetrazoles 11–14 from androstane and estratriene 16,17-seco-16-nitrile-17-mesyloxy derivatives 5–8, via intramolecular 1,3-dipolar cycloaddition from in situ generated 16,17-seco-17-azido-16-nitriles 5a–8a. Products were validated by 1H/13C-NMR, IR, HRMS, and structurally characterized by X-ray crystallography and computational methods. Compounds were evaluated as potential anti-proliferative agents against a panel of human cancer cell lines. D-Homo fused steroidal tetrazoles 13 and 14 appear to have specific, selective anti-proliferative effects against estrogen receptor positive (ER+) breast adenocarcinoma cells, which correlate with binding energies calculated from molecular docking to the estrogen receptor α-ligand binding domain (ERα-LBD). Moreover, molecular docking suggests that D-ring fused steroidal tetrazoles 13 and 14 could bind to ERα-LBD in a manner similar to known anti-estrogenic compounds. Addition of a D-homo fused tetrazole group appears to structurally mimic the hydrogen bonding potential of β-estradiol, suggesting their general utility in designing novel steroidal tetrazole derivatives as anti-estrogens or inhibitors of steroidogenic enzymes.
Steroids | 2015
Katarina M. Penov Gaši; Evgenija A. Djurendić; Mihály Szécsi; János Gardi; János Csanádi; Olivera R. Klisurić; Sanja V. Dojčinović-Vujašković; Andrea R. Nikolić; Marina P. Savić; Jovana J. Ajduković; Aleksandar M. Oklješa; Vesna Kojić; Marija N. Sakač; Suzana S. Jovanović-Šanta
A convenient microwave assisted solvent free synthesis as well as conventional synthesis of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives 7-19 from appropriate steroidal precursors 1-6 and methyl salicylate is reported. The microwave assisted synthesis in most cases was more successful regarding reaction time and product yields. It was more environmentally friendly too, compared to the conventional method. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as their inhibition potency exerted on hydroxysteroid dehydrogenase enzymes (Δ(5)-3βHSD, 17βHSD2 and 17βHSD3). All of the tested compounds were effective in OH radical neutralization, particularly compounds 9, 11 and 14, which exhibited about 100-fold stronger activity than commercial antioxidants BHT and BHA. In DPPH radical scavenging new compounds were effective, but less than reference compounds. 2-Methoxybenzoyl ester 10 exhibited strong cytotoxicity against MDA-MB-231 cells. Most compounds inhibited growth of PC-3 cells, where salicyloyloxy stigmastane derivative 15 showed the best inhibition potency. Compounds 9, 10 and 11 were the best inhibitors of 17βHSD2 enzyme. X-ray structure analysis and molecular mechanics calculations (MMC) were performed for the best cytotoxic agents, compounds 10 and 15. A comparison of crystal and MMC structures of compounds 10 and 15 revealed that their molecules conformations are stable even after releasing of the influence of crystalline field and that the influence of crystal packing on molecular conformation is not predominant.
Journal of Pharmaceutical and Biomedical Analysis | 2017
Lidija R. Jevrić; Milica Ž. Karadžić; Anamarija Mandić; Sanja O. Podunavac Kuzmanović; Strahinja Z. Kovačević; Andrea R. Nikolić; Aleksandar M. Oklješa; Marija N. Sakač; Katarina M. Penov Gaši; Srđan Z. Stojanović
HIGHLIGHTSChromatographic lipophilicity of newly synthesized steroid derivatives was defined using RP HPLC combined with two chromatographic columns.Computational modeling of structures of investigated steroids was carried out.Molecular features influencing the chromatographic lipophilicity were determined and defined.Novel linear and multiple linear QSRR models were generated.Novel classification of investigated steroids was done. ABSTRACT The present paper deals with chromatographic lipophilicity determination of twenty‐nine selected steroid derivatives using reversed‐phase high‐performance liquid chromatography (RP HPLC) combined with two mobile phase, acetonitrile‐water and methanol‐water. Chromatographic behavior of four groups (triazole and tetrazole, toluenesulfonylhydrazide, nitrile and dinitrile and dione) of selected steroid derivatives was studied. Investigated compounds were grouped using principal component analysis (PCA) according to their logk values for both mobile phases. Grouping was in the very good accordance with the polarity and lipophilicity of the investigated compounds. QSRR (quantitative structure‐retention relationship) approach was used to model chromatographic lipophilicity behavior using molecular descriptors. Modeling was performed using linear regression (LR) and multiple linear regression (MLR) methods. The most influential molecular descriptors were lipophilicity descriptors that are important for molecules ability to pass through biological membranes and geometrical descriptors. All established LR‐QSRR and MLR‐QSRR models were statistically validated by standards, cross‐ and external validation parameters as well as with two graphical methods. According to all these assessments, MLR models were better for chromatographic lipophilicity prediction. It was shown that chromatographic systems with methanol‐water were better for modeling of logk than systems with acetonitrile‐water, as well as the systems that contained lower volume fractions of organic component in mobile phase. Modeling was performed in order to obtain lipophilicity profiles of investigated compounds as future drug candidates of biomedical importance.
European Journal of Pharmaceutical Sciences | 2017
Milica Ž. Karadžić; Lidija R. Jevrić; Anamarija Mandić; Siniša L. Markov; Sanja O. Podunavac-Kuzmanović; Strahinja Z. Kovačević; Andrea R. Nikolić; Aleksandar M. Oklješa; Marija N. Sakač; Katarina M. Penov-Gaši
ABSTRACT Physicochemical characterization of steroid analogs (triazole, tetrazole, toluenesulfonylhydrazide, nitrile, dinitrile and dione) is considered to be a very important step in further drug selection. This study applies to the determination of lipophilicity of previously synthesized steroid derivatives using reversed‐phase high‐performance liquid chromatography (RP HPLC). Chemometric aspect of chromatographic lipophilicity is given throughout multiple linear regression (MLR) quantitative structure‐retention relationships (QSRR) approach. Minimal inhibitory concentration (MIC) is determined for two steroid derivatives possessing antimicrobial activity against Staphylococcus aureus. Molecular docking study was performed in order to identify the compound with the most promising potential as human cytochrome P450 CYP17A1inhibitor. Identified 3&bgr;‐hydroxyandrost‐5‐eno[16,17‐d]‐1,2,3‐triazole (I.2.) could be recommended for further trials for anticancer drugs and subjected to the absorption, distribution, metabolism, excretion and toxicity (ADMET) evaluation. Graphical Abstract Figure. No Caption available.
Steroids | 2018
Andrea R. Nikolić; Ivana Kuzminac; Suzana S. Jovanović-Šanta; Dimitar Jakimov; Lidija D. Aleksić; Marija N. Sakač
HIGHLIGHTSSteroidal 6‐substituted 4‐en‐3‐one D‐seco dinitriles are synthesized.Most of the tested compounds express strong antiproliferative activity against HeLa and/or MDA‐MB‐231.Apoptosis induction in the treated MDA‐MB‐231 and HeLa cells is revealed. ABSTRACT Steroidal 16,17‐seco‐16,17a‐dinitriles possessing 4‐ene‐3,6‐dione (3), 6‐methylene‐4‐en‐3‐one (5), (6E)‐hydroxyimino‐4‐en‐3&bgr;‐ol (9) or (6E)‐hydroxyimino‐4‐en‐3‐one (10) moiety were synthesized starting from 3&bgr;‐acetoxy‐16,17‐secoandrost‐4‐ene‐16,17a‐dinitrile (1). Antiproliferative activity of the newly synthesized compounds, as well as previously synthesized 3‐oxo‐16,17‐secoandrosta‐1,4‐diene‐16,17a‐dinitrile (VII), was tested in vitro. Compound 9 displayed submicromolar antiproliferative activity against human cervical carcinoma (HeLa) cells (IC50 0.48&mgr;M), and compounds 3 and 10 expressed strong inhibitory potential against HeLa cells (IC50 4.31&mgr;M and 2.64&mgr;M, respectively). Also, compound 10 was effective in inhibiting estrogen hormone‐independent (MDA‐MB‐231) cells (IC50 2.78&mgr;M). All tested compounds had no influence on the proliferation of healthy cells (MRC‐5). Since MDA‐MB‐231 breast cancer cells and HeLa cervical cancer cells were most sensitive to treatment by 16,17‐seco‐16,17a‐dinitriles, apoptosis induction after treatment by compounds 3, VII, 9 and 10 was studied in these cells, to reveal the mechanism underlying cell growth inhibition. All tested compounds significantly induced apoptosis in both treated cell lines, which was evident from results obtained by a double AO‐EB staining test and quantified by counting cells with apoptotic morphology after staining with Giemsa dye. Among all tested substances, (6E)‐hydroxyimino‐4‐en‐3‐one derivative 10 expressed the most proapoptotic activity.
Steroids | 2018
Sofija S. Bekić; Maja A. Marinović; Edward T. Petri; Marija N. Sakač; Andrea R. Nikolić; Vesna Kojić; Andjelka Ćelić
&NA; Synthesis and biological evaluation of steroidal derivatives with anticancer properties is an active area of drug discovery. Here we measured the relative affinities of D‐seco modified steroidal derivatives for estrogen receptor &agr;, estrogen receptor &bgr; or androgen receptor ligand binding domains using an optimized non‐transcriptional fluorescent cell assay in yeast. Ligand binding domains of steroid receptors were expressed in‐frame with yellow fluorescent protein in the yeast Saccharomyces cerevisiae. Addition of known steroid ligands to yeast expressing the appropriate cognate receptor results in increased fluorescence intensity, enabling estimation of receptor binding affinities in a dose‐response and time‐dependent manner. Relative binding affinities of D‐seco modified steroidal derivatives 1–4 were then evaluated using this yeast system by live cell fluorimetry and fluorescence microscopy, coupled with in vitro cytotoxicity and in silico molecular docking studies. D‐Seco estratriene derivative 2displayed strong affinity for both estrogen receptor &agr; and &bgr; ligand binding domains and negligible affinity for the androgen receptor ligand binding domain. Compound 2 also showed moderate cytotoxicity against estrogen receptor positive MCF‐7 breast adenocarcinoma cells. In addition to identification of new ligands for steroid receptors, this assay could also be used to filter out compounds with potential for off‐target interactions with steroid receptors during the early stages of compound screening. Graphical abstract Figure. No caption available. HighlightsA non‐transcriptional fluorescent screen for steroids was optimized in yeast.Compounds with on‐ or off‐target affinity for steroid receptor can be identified.D‐seco estratrienes have affinity for estrogen receptor and MCF‐7 cytotoxicity.
Journal of Research in Physics | 2013
Olivera R. Klisurića; Srđan J. Rakića; Miroslav Cvetinov; Maja Stojanović; Andrea R. Nikolić; Suzana Jovanović Šanta; Ana R. Marković; Ljiljana N. Solomun
Abstract The present study deals with the application of X-ray powder diffraction (XRPD) analysis as a technique for identification of the forms of clopidogrel bisulphate (CLP) present in both the active pharmaceutical ingredients (API) and tablets, specifically addressing the question of whether API converts to another form after 12 months of storage. The investigation of the possibility of phase transitions occurring over a temperature range spanning from room temperature to the melting point, both in tablets and pure CLP, were also performed. Tablet samples were observed for the changes in their structure using polarizing optical microscopy, which was also used to determine the melting points of tablet samples. The results gained during this work confirm that XRPD is applicable for API and tablets testing. This is particularly important if we take into account that the method can be used during stability studies, i.e. in order to test the quality of tablets during the validity period.
Structural Chemistry | 2016
Olivera R. Klisurić; Mihály Szécsi; Evgenija A. Djurendić; Szabó Nikoletta; Bianka Edina Herman; Suzana Jovanović Šanta; Sanja V. Dojčinović Vujašković; Andrea R. Nikolić; Ksenija Pavlović; Jovana J. Ajduković; Aleksandar M. Oklješa; Edward T. Petri; Vesna Kojić; Marija N. Sakač; Katarina M. Penov Gaši
World Academy of Science, Engineering and Technology, International Journal of Chemical and Molecular Engineering | 2017
Milica Karadzic; Lidija R. Jevrić; Sanja O. Podunavac-Kuzmanović; Strahinja Z. Kovačević; Siniša L. Markov; Aleksandar M. Oklješa; Andrea R. Nikolić; Marija N. Sakač; Katarina M. Penov Gaši