Synthesis Study Of MDV3100as Androgen Receptor Antagonist

Internationally, prostate cancer (PCa) is the second most common cancer diagnosed among men (behind lung cancer), and is the sixth most common cause of cancer death among men. In2008,903,500men were diagnosed with prostate cancer and258,400men died of it. Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in males in America, accounting for27%of the total new cancer cases and10%of the total cancer deaths in males. The incidence of prostate cancer in China has recently increased substantially due to earlier diagnosis. It will become a common disease affecting men’s health in China in the future.Early-stage prostate cancer is sensitive to androgen deprivation therapy (ADT) including surgical and medical castration. Combined androgen blockade therapy with antiandrogens and androgen deprivation therapy is effective and used for the treatment of early-stage prostate cancer. However, cancer cells escape such androgen blockade therapy and patients invariably progress to a castration-resistant state after long term of this treatment. The progression to castration-resistant prostate cancer (CRPC) involves the complex interplay of a network of signaling molecules that collectively promote net cell proliferation relative to cell death. Mutations and over-expression of the androgen receptor (AR) are highly responsible for this progression. The fact that this progression is associated with an active AR signaling pathway reveals that AR is still a key molecular target of drug development for treatment of PCa. AR is a steroid hormone receptor member of the larger nuclear receptor family and a ligand-activated transcription factor consisting of919amino acids. The ligand binding domain (LBD) at C-terminal of the AR structure is responsible for recognition and binding of ligands. Upon androgen binding, AR goes through a series of conformational changes which will finally activate the transcription of AR gene. By competitively binding to AR, antiandrogens can antagonize actions of androgens and have therapeutic effect for the treatment of PCa.MDV3100(enzalutamide) is the first novel antiandrogen targeting the C-terminal LBD to emerge from a chemical structure-activity relationship program designed to develop more potent antiandrogens. It has been approved by the FDA and EMA in2012and2013respectively for use in prostate cancer patients who have been previously treated with docetaxel. As an AR antagonist, MDV3100can competitively inhibit androgen binding to AR and AR nuclear translocation and interaction with DNA. The final results of the registration trial showed a37%reduction in the risk of death for patients treated with MDV3100relative to placebo. The treatment was well-tolerated, with common side effects including fatigue, diarrhea, and hot flashes.We reviewed and summarized the only three synthetic schemes of MDV3100reported so far in this article. By summarizing and analyzing the three schemes, we found disadvantages in some synthetic steps. To get the compound and improve the synthetic methods, we synthesized MDV3100referring to two of the synthetic routes and moderately change the synthetic methods of some steps. Finally we got the compound MDV3100, whose structure was confirmed by high-performance liquid chromatography (HPLC), elemental analysis, infrared spectrophotometry (IR), ultraviolet-visible spectrophotometry (UV), nuclear magnetic resonance (NMR), high resolution mass spectrometer (HRMS), X-ray powder diffraction and simplified the reaction conditions and following treatments, reduced the use of reagents and reactants with great toxicity and improved the reaction yield of specific steps.