Progress Towards the Synthesis of Novel Immunosuppressive Agent FR252921
Calcineurin inhibitors have been the mainstay in transplantation medicine. They revolutionized the field of tissue and organ transplantation since their first introduction in the 1970’s. However, many studies have pointed out that CsA and FK506 also present complications such as: acute nephrotoxicity, hypertension, neuropathy and hepatotoxicity. The life expectancy of patients who have recently received a transplanted organ diminishes as they are exposed to these complications over the years. The immune system is a relentless fighting machine, T-cell mediated immune response must be regulated down to avoid organ rejection. Many reports mention APC activity (B cell, dendritic cell, and macrophages) plays a major role in tissue and organ rejection. Unfortunately, CN inhibitors: CsA and FK506 are insufficient to suppress APC function and activity. In 2003, Fujine et al. isolated FR252921 from the culture broth of Pseudomonas fluorences. It is a novel immunosuppressive agent that inhibits anti-CD3 mAb stimulated splenocyte proliferation specific for T-cells just as CsA and FK506, but also inhibits LPS stimulated splenocyte proliferation specific for B cells, dendritic cells, macrophages in vitro (IC50 = 7.0 nM, lymphocyte, cell line). In this presentation, we will describe our efforts to synthesize FR252921 by incorporating two unique methodologies. The first one: is a Lewis–acid catalyzed tetrahydrofuran ring opening reaction, that give us access to the dipeptide core structure of FR252921 and the anti-aldol moiety on C11-N15 with the right 12(S), 13(R) configuration. The second methodology is: a diastereoselective Braun’s acetate aldol reaction, that gives us access to the β-hydroxy acid fragment on C16-C11’ with the right 18(R)-configuration. In the final stages of the synthesis, unlike all four previous approaches, we rely on an intramolecular HWE olefination reaction and not on a Yamaguchi or Shiina macrolactonization for the cyclization of the 19-membered macrolactone. We planned to attach the side chain via a late stage Julia olefination once the core has been synthesized.
Ghosh, Purdue University.
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