Synthesis of Resolvin D1 and Analogs as Potential Anti-Angiogenetic Agents
Treatment with ω-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is known to be beneficial in a wide range of inflammatory disorders. Recently, the potential efficacy of ω-3 PUFAs in the inhibition of tumor angiogenesis was reported.
Structure of the polyunsaturated compound Resolvin D1.
Angiogenesis is a process of tissue vascularization that involves the growth of new developing blood vessels into a tissue. This process is also referred to as neo-vascularization.
Oxygen and nutrients are supplied to living tissues via blood vessels. Angiogenesis has been reported to be critical for reproduction, development and wound repair.
However, inappropriate angiogenesis, also referred to as pathological angiogenesis, can have severe negative consequences. Excessive blood vessel proliferation can result in tumor growth, tumor spread, blindness, psoriasis and rheumatoid arthritis.
An attractive anti-cancer strategy could be accomplished if excessive blood vessel proliferation of a tumor would be retarded by inhibition of angiogenesis since a tumor must continuously stimulate the formation of new capillary blood vessels for its growth.
Several lipid mediators biosynthesized from PUFAs have been reported. These lipid mediators include three new classes of compounds:
- Lipoxins derived from arachidonic acid
- Resolvins of the D-series from DHA and resolvins of the E-series from EPA
- Protectins derived from DHA.
Recent findings have shown that these lipid mediators are produced actively during the resolution phase of inflammation to reestablish normal homeostasis. Although the contribution of these lipid mediators in the resolution of inflammation and maintenance of homeostasis has been established in several disease models, their relative efficacy in the modulation of angiogenesishas not been investigated systematically. However, Serhan and coworkers recently reported that resolvins of the D-series significantly down regulated the expression of angiogenetic growth factors and their receptors.Moreover it was also reported that resolvin D1 protected against retinopathy with reductions in vaso-obliteration and neovascularization. The protective effect displayed by these lipid metabolites was mediated, in part, through suppression of tumor necrosis factor-a (TNF-a).