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Overview
The ongoing development of therapeutic treatments, such as bioactive molecules and gene therapies, demands new mechanisms with which to deliver them to the specific target area(s) within the body. Site-targeted delivery of therapeutic drugs has several advantages over oral administration, including prolonged deposition of the active agent at the specific target site, at high concentrations and with a reduced risk of remote systemic toxicity.
The goal is therefore to develop efficient delivery systems, which can deploy sensitive medications intact and at specific sites within the body in a controlled and predictable fashion. In addition to controlled drug elution, such systems must also exhibit excellent biocompatibility, chemical stability and the correct physical properties to ensure suitability for their specific application.
In order to meet these demanding requirements, BioInteractions has developed the Adapt™ Biostable Drug Delivery Platform
Rapamycin Analogues
Rapamycin (Sirolimus) is the metabolic product of the fungus Streptomyces hygroscopicus. It is a macrocyclic lactone that has demonstrated potent anti-fungal, immunosuppressant and anti-proliferative activity and was approved by the U.S. Food and Drug Administration (FDA) in September 1999 for the use in renal transplant rejection. Rapamycin is described as cytostatic as it arrests cell-cycle progression at the G1/S phase, thus inhibiting cellular proliferation.
The unique mode of action involves firstly the binding of rapamycin to the cytosolic protein FK506 binding protein 12 (FKBP-12) to afford a rapamycin:FKBP-12 complex. This dimeric complex then binds to and deactivates the protein kinase, mammalian target of rapamycin (mTOR). mTOR is a key effector of signals mediated by the phosphatidylinositol 3-kinase (PI3-K) pathway and also initiates growth and proliferation in response to nutrients.
As a result of rapamycin's unique mode of action and broad range of activity a great deal of research has been carried out in recent years, focused towards the preparation of rapamycin analogues with enhanced activity. Early attempts to afford rapamycin analogues with enhanced activity often resulted in a loss of binding affinity and/or immunosuppressive activity. However, modification of the cyclohexyl region, particularly the hydroxyl group at the C43 position, has led to the development of novel derivatives with good activity.
Direct acylation of rapamycin at the C43 position, in a regioselective fashion, has proved problematic owing to the fact that rapamycin possesses two secondary hydroxyl groups (C28 and C43). Therefore, the development of novel synthetic strategies to achieve this transformation have been sought.
Rapamycin Carbonate Esters
BioInteractions has developed a novel synthetic strategy to afford rapamycin carbonate esters at the C43 position with complete regioselectivity. A range of adducts have been furnished and initial in-vitro testing is underway to determine the efficacy of these analogues for the treatment of conditions such as cancer and restenosis.
For more information or to collaborate on this project please Contact Us.
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Rapamycin (Sirolimus) |
