Dexamethasone synthesis

Manz, B., Heubner, A., Kohler, I., Grill, H. J., and Pollow, K. (1983). Synthesis of biotin-labeled dexamethasone derivatives. Novel hormone-affinity probes. Eur.J. Biochem. 131,... 

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. 

Diosgenin (Fig. 4) is a steroid sapogenin produced by Dioscorea species. This natural product is used as a precursor for the commercial synthesis of medicinal steroids such as prednisolone, dexamethasone, norethisterone, and metenolone, among others. Microtuber-derived cell suspensions of Dioscorea doryophora were able to accumulate diosgenin at concentrations as high as 3.5% g dw. Embryogenic callus of Tribulus terrestris were also able to accumulate diosgenin (170.7 1.0 pg/g dw). ... 

Figure 4.4. The chemical synthesis of dexamethaso-ne-HSA. Dexamethasone hemisuccinate is first converted to a reactive intermediate with isobutylchlorocarbonate and is then coupled to the free E-NH2 of the lysine residues in human serum albumin (HSA).

Fluorocorticoids are produced on the ton-scale (e.g., 1.1 tons of fluticasone in 2001). The industrial production of fluorocorticosteroids has been a triple chemical challenge availability of the starting material, use of hazardous and toxic fluorination reagents, and a large number of chemical or biotechnological steps involved in the synthesis, as highlighted by the synthesis of dexamethasone (Figure 8.45). 

This group of disorders is characterized by specific defects in the synthesis of cortisol. In pregnancies at high risk for congenital adrenal hyperplasia, fetuses can be protected from genital abnormalities by administration of dexamethasone to the mother. The most common defect is a decrease in or lack of P450c21 (2ll3-hydroxylase) activity. ... 

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17a-hydroxylase (P450cl7) and 17,20-lyase (Figure 39-1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refractory prostate cancer. 

Antinflammatory DMARDs such as chloroquine, auranofin, sodium aurothiomalate, and dexamethasone have been shown to inhibit IL-1 synthesis [89]. Analogs of these compounds have exhibited potent inhibition of IL-1 a- induced cartilage resorption [90]. Elevated collagenase and proteoglycanase levels caused by IL-1 in human cartilage were found to be reduced by tiapro-... 

Fibrinogen synthesis is stimulated by hormones such as the glucocorticoid dexamethasone or suppressed by the estrogen estadiol-17 (Amrani et al., 1983 Wangh et al, 1983). The three fibrinogen genes share a... 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

Aminoglutethimide [ah me no glue TETH i mide] is useful in second line therapy for the treatment of metastatic breast cancer. It inhibits the adrenal synthesis of pregnenolone from cholesterol, and the extra-adrenal aromatase reaction responsible for the synthesis of estrogen from androstenedione. Aminoglutethimide is administered orally, and is metabolized by the hepatic cytochrome P-450 system to inactive products. Because of its ability to induce this system, its own metabolism is accelerated, and interactions that increase the metabolism of dexamethasone (see p. 275), theophylline (see p. 220) and digoxin (see p. 158) can occur. Aminoglutethimide causes transient CNS depression and a maculopapular rash. 

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