Drug synthesis, thalidomide

Keywords Asymmetric synthesis Drug synthesis Teratogenicity Thalidomide... 

More recently this procedure has been used for a new synthesis of thalidomide, now a rehabilitated drug [94] (Scheme 8.68). 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

Reepmeyer JC, Cox DC (1987) FDA monograph guidelines to thalidomide synthesis. US Food Drug Administration, Washington, DC... 

Directly (thalidomide, cytotoxic drugs, antithyroid drugs, aromatic retinoids, e.g. isotretinoin) any drug affecting cell division, enzymes, protein synthesis or DNA s)mthesis, is a potential teratogen, e.g. many antimicrobials. 

Biologically active compounds usually have at least one asymmetric centre and dramatic differences in the activities of different enantiomers of chiral drugs are commonly observed (see Box 23.6). Whereas one enantiomer may be an effective therapeutic drug, the other may be inactive or highly toxic as was the case with thalidomide. Asymmetric synthesis is therefore an active field of research. 

The thalidomide tragedy, described in chapter 7, started to focus the pharmaceutical industry on synthesis of single enantiomers rather than racemic mixtures. Even if there are no antagonistic or undesirable side effects from the other enantiomer, a racemic mixture may waste 50 percent of the mass of a drug. Optically pure compounds such as vitamin B]2, morphine, and L-dopa are available naturally. In some cases (e.g., vitamin B12), the natural source is really the only practical source. For simpler compounds like L-dopa, chemical synthesis is very practical but resolution of enantiomers may double the production cost. 

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