Active compound development

The development of naturally occurring active compounds into commercially viable drugs follows the lines outlined in Chapter 16. However, the stereochemistry of many naturally occurring drugs and the analogues derived from these compounds is so complicated that their large-scale commercial synthesis from synthetically manufactured starting materials is not economically viable. In these instances it is sometimes possible to grow sufficient quantities of a plant or microorganism that contains a compound whose structure contains the required stereochemistry. This naturally occurring compound is used as the starting point for the required drug. For example, in the mid-twentieth century it was discovered that cortisone and hydrocortisone (cortisol) (Fig. 6.8) were highly effective in cases of rheumatoid arthritis. Both of these drugs, like most steroids, have a large number of stereochemical centres that make their synthesis difficult (see section 15.3). Cortisone was originally extracted from the adrenal glands of cattle and eventually, using a laborious 30-step synthesis, from deoxycholic acid isolated from ox bile. These production methods could not meet the demand for these drugs and so alternative more efficient semisynthetic methods were developed. Originally hecogenin obtained from sisal leaves was used as the starting material but this has now been superseded by semisynthetic methods based on progesterone produced from diosgenin isolated from Mexican yams (Fig. 6.8). Progesterone has the same stereochemistry of rings A, B and C as cortisone and hydrocortisone. The synthesis starts with the conversion of diosgenin to progesterone. Progesterone is fermented with Rhizopus arrhizus or R. nigricans to form 11a-hydroxyprogesterone in greater than 85 per cent yield. A series of reactions convert this compound into compound A, the precursor of both cortisone ethanoate and hydrocortisol ethanoate. It is interesting to note that cortisone is metabolised in the liver to hydrocortisol, which is the active agent.

OH O

Figure 6.7 A flavone isolated by Garo et al. from the dichloromethane extract of Monotes engleri using a combination of LC-NMR, LC-MS and LC-UV

chemical steps chemical steps

Diosgenin

Various chemical steps

Fermentation using either Rhizopus arrhizus or R. nigricans

Various chemical steps

Various chemical steps

Fermentation using either Rhizopus arrhizus or R. nigricans

Various chemical steps

O OH

Cortisone

O"

Hydrocortisone (cortisol)

Figure 6.8 An outline of a semisynthesis of cortisone and hydrocortisone from Mexican yams

Cortisone

O OH

O"

Hydrocortisone (cortisol)

Figure 6.8 An outline of a semisynthesis of cortisone and hydrocortisone from Mexican yams

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