Immunosuppressive agents, examples

A variety of medical conditions exist that are caused or exacerbated by the immune system itself. These are usually treated by administering immunosuppressive agents. Examples include ... 

Cytotoxic agents Since proliferation of cells is essential for the immune response, agents that inhibit DNA synthesis have been used as immunosuppressive agents for many years. The first were used in the 1960s, particularly to prevent rejection of a transplanted organ, for example purine and pyrimidine analogues. These agents are not now used in autoimmune diseases but are stiU used in cancer chemotherapy (Chapter 21). 

The antithymocyte globulin (ATG) Fresenius S, produced in rabbits, is an example of a polyclonal antibody mixture used in immunosuppressive therapy in combination with other immunosuppressive agents (e.g., cyclosporine, prednisone) after organ transplantation. 

Danishefsky and coworkers have demonstrated the conversion of lactones to carbocycles by the 3,3-sigmatropic shift of silylketene acetals. Jq the total synthesis of the Fusarium toxin equisetin, for example, keto lactone (138) was converted to its bissilyl derivative (139) by reaction with 2 equiv. of LDA and an excess of TMS-Cl. In situ thermolysis of ketene acetal (1 ) led to a very smooth transformation into ester (140), which was carried on to equisetin (Scheme 26). This methodology was also applied by Schreiber and Smith in the preparation of the cyclohexyl moiety of the immunosuppressive agent FK-506. Ireland-Claisen rearrangement of silylketene acetal (142), prepared by treatment with TBDMS-OTf and triethylamine at low temperature, provided, after hydrolysis of the silyl ester, the carboxylic acid (143) in 71% overall yield (Scheme 27). The strict translation of configuration via a boatlike transition state is typical for this permutation. 

There is indirect evidence of sex differences in immunology. Women have a higher incidence of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The influence of sex hormones on the immune system may provide insight into these immunological disorders. For example, estrogen stimulates both humoral and cell-mediated immunity, whereas testosterone has the opposite effect (126). Therefore, it is not surprising that there is sex-dependent variability in response to immunosuppressive agents. 

Reports of delayed transfusion reactions continue to appear and confirm the difficulty of diagnosis. Many allo-antibodies responsible for delayed reactions of various severity have been demonstrated (61,63-69). The specificities include the usual Kidd and Rh antigens/anti-bodies and anti-S. Delayed reactions to the Kell antigens, for example Js(a,b), have been reported (68,69), and anti-FF(b) has also been found to cause a delayed reaction (63). A delayed reaction may occur because of anti-Al production from the group O graft and the reduction of suppressor cell activity by immunosuppressive agents (70). In sickle cell patients a more severe delayed transfusion reaction can be misdiagnosed as sickle cell crisis (71,72). This occurs particularly in patients with U variants (73). 

Since then, both natural and unnatural cyclic peptides have become important synthetic targets because of their potential applications as antibiotics and other therapeutic agents [50-54]. Selected examples include anticancer agents (ADH-1), antibiotics (colistin), growth hormone inhibitors (octreotide), and immunosuppressant agents (cyclosporine A) (Fig. 6) [55]. 

Direct site-selective functionalization of natural products is a powerful tool for the discovery of drug candidates because nature provides a rich pool of unique molecular frameworks with diverse biological profiles [32,33], Acylation of a particular hydroxy group among multiple hydroxy groups in polyol natural products has been well studied by means of enzymatic protocol [34], For example, acylation of rapamycin, an immunosuppressive agent, took place at C(42)-OH selectively in the presence of PSL-C to provide an anticancer agent, temsirolimus (Scheme 13) [35]. Inspired by these achievements, extensive efforts have been devoted to develop the non-enzymatic counterparts toward site-selective functionalization of polyol natural products [4],... 

It has been estimated that well over 300,000 secondary metabolites exist, and it s thought that their primary function is to increase the likelihood of an organism s survival by repelling or attracting other organisms. Alkaloids, such as morphine antibiotics, such as erythromycin and the penicillins and immunosuppressive agents, such as rapamycin (sirolimus) prescribed for liver transplant recipients, are examples. 

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