Prodrugs oxidative reactions

The diazeniumdiolate anions react with electrophiles to produce stable covalent compounds (Fig. 3.9) [213, 216]. These compounds have the ability to act as prodrugs, releasing nitric oxide only when metabolically or enzymatically converted to the diazeniumdiolate anion [217-219]. Several compounds ofthis class have been synthesized by reaction of alkyl or aryl halides, sulfate esters, epoxides, etc. with the ionic diazeniumdiolates [220, 221]. 

A further condition for good brain delivery, one that is particularly relevant in the present context, is that e) direct hydrolysis of the dihydropyridine pro-prodrug (Fig. 8.14, Reaction c) does not compete with oxidation, especially in the periphery, since this would decrease the amount of CDS available for brain delivery. In fact, the pyridinium metabolite is more susceptible than the dihydropyridine pro-prodrug to alkaline and enzymatic hydrolysis, since the carbonyl C-atom of the pyridinium compound (B, Fig. 8.15) is much more electrophilic than that of the dihydropyridine (A, Fig. 8.15). 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

A retro hetero Diels-Alder reaction to release an anthracene derivative 9-9 and nitroxyl (HNO) from the corresponding cycloadduct 9-8 by a catalytic antibody has been described by Reymond and Lerner [565]. As a haptene the acridinium salt 9-10 was used (Fig. 9-3). The antibody obtained is of great biological interest as a prodrug release system since the liberated nitroxyl is easily oxidized by the ubiquitous enzyme superoxide dismutase to give nitric oxide (NO) which acts as a chemical messenger for several important bioregulatory processes. 

The abundance of oxidizing enzymes in the body has made this type of bioaclivation a popular route. Isozymes of cytochrome P-4S0 can oxidize a wide variety of functionalities. generally to produce more polar compounds that can be excreted directly or undergo phase 2 conjugation reactions and. subsequently undergo elimination. This occurs in a fairly predictable manner and, therefore, has been successfully exploited in prodrug approaches. 

Hypoxia-Selective S-Oxide-Containing Prodrugs The metabolic fate of sulfoxide (5-oxide) has been shown to be different under aerobic or anaerobic conditions. Under anaerobic conditions, sulfoxides (24a) can be reduced to sulfides in a reversible reaction (24b) (Scheme 12).3 Under aerobic conditions, sulfoxides (24a) are oxidized to sulfones (24), a process that is not reversible (Scheme 12). 

The following examples illustrate the bioprecursor-prodrug approach, although the intentional use of bioprecursor design is relatively recent and, in some cases, there are some doubts about the prospective or the retrospective character of the design. The hrst examples relate to oxidative bioactivations they are followed by examples of reductive bioactivations and dually by non-redox reactions. Often, however, the active species results from a cascade of metabolic reactions involving oxidative as well as reductive processes, complicated by hydrolytic reactions or hydration-dehydration sequences. 

---