Organs developing semisynthetic

As indicated earlier, plant products can be useful as starting materials for the semisynthetic preparation of other drugs. An important example in this regard is the Mexican yam, which produces a steroid precursor (diosgenin) vital to the synthesis of steroidal hormones used in oral contraceptives (i.e., progesterone). The availability of diosgenin eliminates numerous expensive steps in the organic synthesis of the basic steroid molecule. It was this discovery that contributed to the development of the pharmaceutical company Syntex (now a subsidiary of Hoffman LaRoche) and the development of the first birth control pill. 

For example, molds and bacteria produce substances that prevent other organisms from growing in their vicinity. The famous Penicillium mold led, via the pharmaceutical industry, to penicillin. However, penicillin was not stable in the acidic environment of the stomach, and so compounds were synthesized by chemists to produce a range of useful semisynthetic penicillin analogues. An example of the use of analogues to develop new antibacterial antibiotics is provided in Chapter II-14, on the development of moxifloxacin. 

The most practical method that is used in the industrial synthesis of esomeprazole involves titanium-catalyzed oxidation with an alkyl hydroperoxide, and a dialkyltartrate as chiral ligand, in an organic solvent such as dichloromethane. A variety of oxidoreductases are known to catalyze the enantioselective oxidation of prochiral sulfides, usually as whole-cell biotransformations in aqueous media, but no simple metal complexes have been shown to be effective in water and the development of practical systems employing aqueous hydrogen peroxide as the primary oxidant is still an important challenge. In this context it is worth mentioning the enantioselective sulfoxidation of prochiral sulfoxides catalyzed by the semisynthetic peroxidase, vanadium-phytase, in an aqueous medium. 

One area that illustrates the power of metabolic engineering is the development of alternative routes for the production of 7-amino cephalosporanic acid (7-ACA) and 7-amino deacetoxycephalosporanic acid (7-ADCA), which serves as precursors for the production of semisynthetic cephalosporins. Until recently the sole route for 7-ADCA was by chemical ring expansion of 6-amino peniciUanic acid (6-APA), which can be derived from penicilUns. Thus, many semisynthetic cephalosporins were traditionally derived from penicillin produced by fermentation. With the high potential of -lactam production by P. chrysogenum, it is of interest to engineer this organism to produce the cephalosporins directly by fermentation. 

Sirolimus (rapamycin) (Vezina et al. 1975) is widely used to prevent rejection in organ transplant. It is especially usefiil in kidney transplants because, different from cyclosporine and tacrolimus, it is not a calcineurin inhibitor and therefore is less toxic to the kidney. Sirolimus inhibits T-cell and B-cell activation. It binds to the immunophilin FKproteinl2, and this binary complex inactivates a serine-threonine kinase (mTOR) termed the mammalian target of rapamycin (Huang et al. 2003). The final effect is the arrest at phase G1 of cell cycle progression. This effect occurs not only in T cell and B cells, but it has been observed in many tumor cell lines. Semisynthetic derivatives of rapamycin, suitable for i.v. administration, have been developed as antitumor agents. Temsirolimus was approved by FDA in 2007 for advanced kidney cancer treatment (Hudes 2009). Everolimus was also approved for kidney cancer treatment in 2009 and for organ rejection prophylaxis in 2010. At present, phase III clinical trials are under way in a variety of tumors (Dansey 2006). 

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