[Nescafe]

Hi,

I often see in literature people making pivaloyloxymethyl,acetoxmethyl, methoxymethyl as well as methyl and ethyl esters. The first three are said to be better suited pro-drugs in situations where a more prolonged administration of the agent is required. I understand that this means that these are more resistant to hydrolysis than the methyl and ethyl esters, but how come? Is it a matter of hindrance?

Also, in case of methyl ester, won't we produce methanol as result of the hydrolysis, and isn't methanol toxic? Ethyl ester will just get people drunk afterwards, I don't understand why people make both the methyl and the ethyl either other than it just being "the usual protocol" :S

Just to clarify, I am referring to their enzymatic hydrolysis in cells etc,  not in organic chemistry reactions.

Thanks,

Nescafe.

[Arkcon]

I've moved the topic to Organic Chemistry, given the topic is the stability and reactivity of modifying groups.  To answer your twin issues of the methyl and ethyl ester groups becoming methanol and ethanol inside the body -- yes, that does happen.  You have to consider the milligrams of pharmaceuticals people consume, and compute the quantities of methanol or ethanol produced, to realize that your objection is likely not important.  That doesn't stop wing-nuts from ignoring the quantities involved, and making random claims.  But if you're not a wing-nut, you should trouble yourself to compute the quantities involved.

[orgopete]

This is not an easy question to give a simple answer. My background is in agchem, but I presume pharmaceuticals is similar.

First of all, the metabolic rates are data. You can use this to try to match these rates with other physicochemical parameters to try to identify the mechanism of the hydrolysis. From my experience, our esters did not correspond to a saponification mechanism. I could not decide if it was acid catalyzed or radical reaction. Tert-butyls were quite inert to hydrolysis, but allyl, methylallyl, and dimethylallyl were quite rapid. Methoxylbenzyl were also quite labile. More than one site or enzyme may have been involved. Plants (and soil) may have more or at least different metabolic enzymes than mammals.

We were trying to take advantage of differential rates of hydrolysis. Esters were not active at the enzyme level, but the acids were phototoxic to crops. Methyl esters were as good as anything.