Oxidation of dihydropyridines

FIGURE 24.3 One-electron transfer mechanism of P-450-mediated oxidation of dihydropyridines. (From FP Guengerich, RH Bocker. J Biol Chem 263 8168-8188, 1988. With permission.)... 

The oxidation of dihydropyridine-based chemical delivery systems (CDSs) pioneered by Bodor and co-workers [176] has been discussed in a previous book (Chapt. 13 in [81]). There, we examined the principles by which such compounds function to deliver drugs to the brain. Here, we focus our attention to the last step in the activation of these double prodrugs, namely hydrolysis to release the drug. 

Scheme3.5. Dealkylative oxidation of dihydropyridines [16] and reductive cleavage of cyclobutanes [17].

The basis of the chemistry was the photo-oxidation of dihydropyridines (DHP) and similar materials. It was believed that the oxidation resulted in formation of an aromatic pyridine derivative, which added adhesiveness to the coating surface. A number of dihydropyridine derivatives were prepared from readily available aldehydes and acetoacetic esters. Typical of these was derivative I. 

Although some oxidations of dihydropyridines proceed via pyridinyl radicals, the latter are normally not observable due to the ease of further oxidation to pyridinium ions. By a judicious choice of agents. Land and Swallow succeeded in converting NADH to the radical NAD, and so demonstrated that NAD formed by oxidation... 

Electrochemical oxidation of dihydropyridines [231-233] has mostly been formulated as a loss of 2e and 2H, but a loss of le , IH and a hydrogen atom has also been described [234]. 

Iwasaki, M., Sari, M.-A., Baarnhielm, C. and Berntsson, P. (1991) Oxidation of dihydropyridine calcium channel blocker and analogues by human... 

The precedent set by the P450-catalyzed oxidation of dihydropyridines to radical cations that aromatize by radical extrusion has led to the observation of comparable processes in related structures. Thus, 2,2-dialkyl-1,2-dihydroquino-lines are also oxidized by P450 enzymes to species that Al-alkylate the heme and inactivate the enzjmies. In these reactions, the 2-alkyl substituent of the dihydroquinoline is bound to a nitrogen of protoporphyrin IX, presumably by a mechanism similar to that proposed for the... 

Guengerich, F.P, W.R. Brian, M. Iwasaki, M.A. Sari, C. Baamhielm, and P. Bemtsson (1991). Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 1I1A4. J. Med. Chem. 34, 1838-1844. 

Application of semiempirical and ab initio calculations of molecular orbitals to study of oxidation of dihydropyridines was reviewed with respect to mechanisms of NAD(P)H transformations (94H(37)1373). 

Progress in investigation of oxidation of dihydropyridines and their analogs 07UK27. 

A combination of silica-supported sulfuric acid, sodium nitrite, and wet silica was used as an oxidant for the effective oxidation of dihydropyridines to pyridine derivatives (Zolfigol et al., 2002) (Scheme 5.50). Products were obtained in excellent yields within short reaction times. Niknam et al. (2007) reported the same combination for... 

This activating effect was first observed in breaking the C-C bond—by the example of bis-2-arylindandiones-l,3 [117]. A series of original papers was related to the electroreduction of 1,4-naphthoquinones and their derivatives [118, 119] as well as to the oxidation of dihydropyridines, dihydropyrimidines [120-122], and phenol derivatives on a carbon electrode [123, 124]. Ya.P. Stradyn and R.A. Gavar were apparently the first in the Soviet Union to use in situ combined EC-ESR for... 

Oxidation of Dihydropyridines. Mn(OAc)3 is an efficient oxidizing agent for the conversion of a variety of Hantzsch 1,4-dihydropyridines to their corresponding pyridines (eq 47). ... 

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