Cyclosporins as immunosuppressants

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Microbial natural product chemistiy has generated a number of bioactive natural products. For instance cyclosporine A FK506 and rapamycin are used as immunosuppressants [16]. Other examples of microbial metabolites, having potential biomedical application include antihyperlipidemics, lovastatin and guggulsterone [17, 18]. The crude extracts of Mucor plumbeus exhibited acetylcholinesterase (AChE) enzyme inhibition activity. Our detailed chromatographic work on this crude extract resulted in the isolation of mucoralactone A (11), a novel steroid containing a lactone moeity incorporated in its structure. 

Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005. 

Azathioprine also has applications in certain disorders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophosphamide in the treatment of Wegener s granulomatosis. It has largely been replaced by cyclosporine in immunosuppressive therapy. Relative to other cytotoxic agents, the better oral absorption of azathioprine is the reason for its more widespread clinical use. 

The initial organ transplantation was performed in 1933 when a kidney was transplanted from a cadaver. Total lymphoid irradiation was used for the immune suppression but the tissue was rejected and the patient eventually died. This was followed by the use of corticosteroids as immunosuppressive agents, but unfortunately steroids by themselves also did not produce positive results. In the early 1960s, cytotoxic agents were introduced for immune suppression these were followed by the use of a combination of cytotoxic agents and corticosteroids until the mid-1980s when cyclosporine was discovered by Borel. 

Caine R. Cyclosporine as a milestone in immunosuppression. TransplantProc. 2004 36(suppl) 13S-15S. 

Azathioprine was found to be more potent as immunosuppressive agent than the previously used corticoids and was systematically used in all organ transplantations until the advent of cyclosporine. Another intermediate in this series, allopurinol, inhibits xanthine-oxidase and therefore is used in the treatment of gout. ... 

Manez R, Jain A, Marino IR, et al. Comparative evaluation of tacrolimus (FK506) and cyclosporin A as immunosuppressive agents. Transpl Rev 1995 9 63. 

The mild reaction conditions of the Corey-Kim oxidation reaction make it an excellent choice when the oxidation of an alcohol that is contained within a complex synthetic intermediate is needed. Rapoport has shown this oxidation method to be useful to prepare aldehydes from primary alcohols in several multi-step syntheses. For example, treatment of alcohol 26 with NCS and DMS in toluene provided aldehyde 27 that was ultimately used to construct the (-)-enantiomer of the C-9-amino acid constituent (28) of immunosuppressant drug cyclosporine as well as the naturally occurring (+)-enantiomer after a slight modification.6... 

Fig. 1. The structure of cyclosporin A (CsA), FK506, rapamycin, and FK506 s derivatives. Note the common structural features of FK506, rapamycin, GPI-1046 and V-10,367, while CsA has an entirely different chemical stracture. Despite their structural differences, CsA and FK506, as immunosuppressants, exhibit a nearly identical spectrum of action on T lymphocytes. In contrast, regardless of their stractural similarity, FK506 and rapamycin exhibit quite different spectra of action on T lymphocytes, though both FK506 and rapamycin are powerful immunosuppressants. GPI-1046 and V-10,367 do not have any immunosuppressive activity however, they have neurotrophic activities as do FK506 and rapamycin.

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