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Published on: August 28, 2019
Structural insights into anticancer activity of D-ring modified estrone derivatives using their lipophilicity in
Jovana Trifunović1, Vladan Borčić1, Saša Vukmirović1
1Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000, Novi Sad, Serbia.
Abstract:
Many forms of breast carcinoma are hormone-dependent and therefore development of novel aromatase inhibitors is of particular interest. Since brain metastases are frequent in patients with advanced breast carcinoma, one of the goals of modern drug development is the discovery of drugs with specific pharmacokinetic profile. High performance thin layer chromatography (HPTLC) is often used to determine lipophilicity of the molecules based on their retention constant. As a predictive analysis, multiple linear regression method was performed to connect pharmacokinetic-dependent parameters with independent physicochemical properties such are: RM0 , TPSA and Mw of fourteen D-ring modified oestrone derivatives. Additionally, docking studies were performed. Conducted correlation analysis indicates excellent dependence between experimental RM parameter values and calculated values of pharmacokinetic parameters. Results show sufficient intestinal absorption of all the investigated molecules as well as moderate volumes of distribution and strong affinity for binding to plasma proteins. Crossing blood-brain barrier is predicted to be successful for 11 compounds. The created quantitative structure activity relationship model represents an excellent predictive tool and enables determination of pharmacokinetic properties of examined compounds. Docking analysis defined molecules I3 and II3 to be the best candidates; however, compound II3 violates the Lipinski rule. It has been concluded that molecules with hydroxyl group at C-3 more effectively pass through blood-brain barrier while structures with benzyloxy groups have stronger interactions with CYP1A19. Molecules II2 , II4 , II6 , and II7 are regarded as most suitable candidates for further investigation considering their good pharmacokinetic and docking characteristics. Copyright © 2017 John Wiley & Sons, Ltd.
Insights
Novel aromatase inhibitors for breast cancer are being developed. This study predicts drug properties like blood-brain barrier penetration for fourteen D-ring modified oestrone derivatives using quantitative structure-activity relationship models and docking studies.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Computational Chemistry
Background:
- Hormone-dependent breast carcinoma necessitates novel aromatase inhibitors.
- Brain metastases are a significant challenge in advanced breast cancer treatment.
- Understanding drug pharmacokinetic profiles is crucial for effective drug development.
Purpose of the Study:
- To develop a quantitative structure-activity relationship (QSAR) model for predicting pharmacokinetic properties of novel oestrone derivatives.
- To evaluate the potential of fourteen D-ring modified oestrone derivatives as drug candidates, focusing on blood-brain barrier penetration.
- To identify lead compounds with favorable pharmacokinetic and docking characteristics for further investigation.
Main Methods:
- High-performance thin-layer chromatography (HPTLC) was used to determine lipophilicity (RM values).
- Multiple linear regression analysis correlated physicochemical properties (RM0, TPSA, Mw) with pharmacokinetic parameters.
- Molecular docking studies were performed to assess binding affinities and interactions.
Main Results:
- A robust QSAR model demonstrated excellent correlation between experimental RM values and predicted pharmacokinetic parameters.
- All investigated oestrone derivatives showed sufficient intestinal absorption and moderate distribution volumes.
- Eleven compounds were predicted to successfully cross the blood-brain barrier, with hydroxyl groups at C-3 enhancing penetration.
- Molecules II2, II4, II6, and II7 emerged as promising candidates due to favorable pharmacokinetic and docking profiles.
Conclusions:
- The developed QSAR model is a valuable tool for predicting pharmacokinetic properties of oestrone derivatives.
- Specific structural features, such as hydroxyl groups at C-3, positively influence blood-brain barrier permeability.
- Compounds II2, II4, II6, and II7 warrant further investigation as potential therapeutics for breast cancer, particularly for targeting brain metastases.
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