Preselection of A- and B- modified d-homo lactone and d-seco androstane derivatives as potent compounds with antiproliferative activity against breast and prostate cancer cells - QSAR approach and molecular docking analysis.

The problem with trial-and-error approach in organic synthesis of targeted anticancer compounds can be successfully avoided by computational modeling of molecules, docking studies and chemometric tools. It has been proven that A- and B- modified d-homo lactone and d-seco androstane derivatives are compounds with significant antiproliferative activity against estrogen-independent breast adenocarcinoma (ER-, MDA-MB-231) and androgen-independent prostate cancer cells (AR-, PC-3). This paper presents the quantitative structure-activity relationship (QSAR) models based on artificial neural networks (ANNs) which are able to predict whether d-homo lactone and/or d-seco androstane-based compounds will express antiproliferative activity against breast cancer cells (MDA-MB-231) or not. Also, the present paper describes the molecular docking study of 3β-acetoxy-5α,6α-epoxy- (3) and 6α,7α-epoxy-1,4-dien-3-one (24) d-homo lactone androstane derivatives, as well as 4-en-3-one (15) d-seco androstane derivative, which are compounds with strong or moderate antiproliferative activity against prostate cancer cells (PC-3), and compares them with commercially available medicament for prostate cancer - abiraterone. The obtained promising results can be used as guidelines in further syntheses of novel d-homo lactone and d-seco androstane derivatives with antiproliferative activity against breast and prostate cancer cells.

[1]  Mohammad Hassan Shojaeefard,et al.  Sensitivity Analysis of the Artificial Neural Network Outputs in Friction Stir Lap Joining of Aluminum to Brass , 2013 .

[2]  Chris Morley,et al.  Open Babel: An open chemical toolbox , 2011, J. Cheminformatics.

[3]  V. Kojić,et al.  Synthesis and antitumor activity of new d-seco and d-homo androstane derivatives , 2009, Steroids.

[4]  Emilio Benfenati,et al.  REACH and in silico methods: an attractive opportunity for medicinal chemists. , 2014, Drug discovery today.

[5]  E. Parish,et al.  Design and action of steroidal aromatase inhibitors , 1996 .

[6]  V. Kojić,et al.  Synthesis, structural analysis and antiproliferative activity of some novel D-homo lactone androstane derivatives , 2013 .

[7]  M. Sakač,et al.  An Overview of Partial Synthesis and Transformations of Secosteroids , 2014 .

[8]  M. Neves,et al.  Anticancer steroids: linking natural and semi-synthetic compounds. , 2013, Natural product reports.

[9]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[10]  D. Horsfall,et al.  Evidence for a novel mechanism of androgen resistance in the human prostate cancer cell line, PC-3 , 1995, Steroids.

[11]  Strahinja Z. Kovačević,et al.  Multivariate regression modelling of antifungal activity of some benzoxazole and oxazolo[4,5-b]pyridine derivatives. , 2013, Acta chimica Slovenica.

[12]  Gareth Thomas.  Fundamentals of Medicinal Chemistry , 2003 .

[13]  M. Scotti,et al.  Prediction of Anticancer Activity of Diterpenes Isolated from the Paraiban Flora through a PLS Model and Molecular Surfaces , 2014, Natural product communications.

[14]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[15]  Ajay N. Jain.  Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. , 2003, Journal of medicinal chemistry.

[16]  V. Njar,et al.  Aromatase inhibitors in advanced breast cancer: mechanism of action and clinical implications , 1998, The Journal of Steroid Biochemistry and Molecular Biology.

[17]  QSAR analysis of 2-benzoxazolyl hydrazone derivatives for anticancer activity and its possible target prediction , 2012, Medicinal Chemistry Research.

[18]  E. Scott,et al.  CYTOCHROME P450 17A1 STRUCTURES WITH PROSTATE CANCER DRUGS ABIRATERONE AND TOK-001 , 2011, Nature.

[19]  D. Skropeta,et al.  Bioassays for anticancer activities. , 2013, Methods in molecular biology.

[20]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[21]  R. D. Bruno,et al.  17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response , 2008, Molecular Cancer Therapeutics.

[22]  K. Héberger,et al.  Ranking of QSAR Models to Predict Minimal Inhibitory Concentrations Toward Mycobacterium tuberculosis for a Set of Fluoroquinolones. , 2010, Acta chimica Slovenica.

[23]  J. Dearden,et al.  QSAR modeling: where have you been? Where are you going to? , 2014, Journal of medicinal chemistry.

[24]  V. Kojić,et al.  Synthesis and Biological Evaluation of Some A,D-Ring Modified 16,17-Secoandrostane Derivatives , 2008 .

[25]  Emilio Benfenati,et al.  An alternative QSAR-based approach for predicting the bioconcentration factor for regulatory purposes. , 2014, ALTEX.

[26]  Strahinja Z. Kovačević,et al.  Non-linear assessment of anticancer activity of 17-picolyl and 17-picolinylidene androstane derivatives--chemometric guidelines for further syntheses. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[27]  M. Sakač,et al.  Synthesis, X-ray structural analysis, and cytotoxic activity of some new androstane d-homo lactone derivatives , 2012, Structural Chemistry.

[28]  M. Sakač,et al.  Synthesis and anti-aromatase activity of some new steroidal D-lactones , 2005, Steroids.

[29]  V. Kojić,et al.  Synthesis and biological evaluation of some new A,B-ring modified steroidal d-lactones , 2008, Steroids.