الفهرس 
Introduction and aim of the work………………………………………….Only 14 pages are availabe for public view
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Abstract
Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically essential properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and such synthetic modifications have confirmed many structure-activity relationships. Several studies demonstrate that steroidal heterocyclic derivatives can be useful in the prevention and treatment of many types of hormone-dependent cancers.
The used materials and methods can be summarized in the following:
1- Structure-based Drug Design
Using Visualization software (Chimera and Maestro), and Docking software (Dock6, AutoDock4, AutoDockVina, rDock, GlamDock, Glide, Plants and Gold software).
1- Aromatase inhibitor (3EQM)
2- Androgen receptor (2AMA)
3- Vitamin D receptor (1DB1)
4- Enzyme inhibitor
CYP24A1 (3K9V)
CYP17A1 (3RUK)
2- Cytotoxic activity using MTT assay
MTT assay against breast (MCF-7), liver (HepG2), lung (A549), and leukemia (ThP-1) cancer cell lines and non-cancerous ones (MDCK and GMSC) measuring the cell viability and IC50 values in both single and combined therapy.
3- Molecular biology assay
After treatment, cell pellet was collected, RNA was extracted, cDNA was obtained, and Real-time PCR reaction for P53, BAX, PUMA and MDM2 human genes with the ACTB (B-Actin) as the reference gene.
And the obtained results can be summarized in the following:
1- Using the computer-aided drug design, the tested steroidal heterocyclic derivatives showed a significant similar binding mode inside the receptor binding site and good ligand-receptor interactions in terms of hydrogen bonds and lipophilic interactions with the key amino acid residues indicating they can perform the same biological activity like the original ligands of the target proteins as aromatase inhibitor, androgen receptors, enzyme inhibitor (CYP 24A1 and CYP 17A1), and the vitamin D receptor, which are the most common mechanisms for the anti-cancer activity of steroidal derivatives. It was found that compound 4 has the best docking score in both androgen receptor and aromatase inhibitor molecular targets and this might explain the mechanism of action for the tested biological activity.
2- Using MTT proliferation assay, the tested compounds showed anti-proliferative activity against a panel of cancer cell lines (breast, liver, leukemia, and lung), meanwhile they are safe (non-toxic) against the normal cell line, and in a combined therapy with the 5-FU, there is an increase in the anti-proliferation activity which proves the chemotherapeutic activity of the tested compounds.
3- Using the molecular biology for elucidation of the mechanism of action of one of the active leads, we concluded the mild apoptosis pathway for the activity of the rested compound.
So it can be concluded from these results, the importance of androstane as steroid nucleus by incorporating different heterocyclic compounds as biologically important pharmacophores to improve cytotoxicity and enhance anti-cancer activity by showing the relationship between chemical structure and biological efficacy which may be necessary for designing new potent chemotherapeutic anti-cancer drugs shortly for the sake of finding more active and selective agents.