Dihydropyridine/pyridinium redox

Fig. 8 Schematic representation of dihydropyridine-pyridinium redox delivery system. (From Ref. 66)...

A. El-Koussi, N. Bodor, Improved Delivery through Biological Membranes. XXV. Enhanced and Sustained Delivery of Trifluorothymidine to the Brain Using a Dihydropyridine <-> Pyridinium Salt Type Redox Delivery System , Drug Design Delivery 1987,... 

Prokai, L. Hsu, B.-H. Farag, H. Bodor, N. Desorption Chemical Ionization, Thermospray, and FAB-MS of Dihydropyridine - Pyridinium Salt-Type Redox Systems. Anal. Chem. 1989, 61, 1723-1728. 

Figure 16.2 Dihydropyridine-pyridinium salt redox system for site-specific and sustained delivery to the brain. The prodrug A is delivered directly to the brain, where it is oxidized and trapped as the prodrug B. The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with sustained release of the biologically active phenylethylamine C and the facile elimination of the carrier molecule D. Elimination of the drug from the general circulation is by comparison accelerated, either as A or B or as cleavage products...

Heterocyclic redox couples do not differ in any profound chemical sense from other hydride donors discussed here. Practical aspects such as reasonable stability of both partners of the redox pair as well as synthetic accessibility, do play a major role, however. In the majority of cases a (hetero)aromatic cation is formed, the developing aromaticity being the driving force for the loss of hydride. By far the most used couple is the dihydropyridine/pyridinium salt (or pyridine) combination already discussed. 

The 1,4-dihydropyridine/pyridinium salt couple is by far the most common six-membered heterocyclic ring redox couple. Other combinations are possible, for example pyrimidines and pyrazines. However, the dihydro forms tend often to be poorly defined, consist of more than one regioisomer, and/or are too reactive to be readily handled. 

Ai-methylpyridinium-2-carbaldoxime (2-PAM = a Figure 36.30b) constitutes the most potent reactivator of acetylcholinesterase poisoned by organophosphorus acylation. However, due to its quaternary nitrogen, 2-PAM penetrates the biological membranes poorly and does not appreciably cross the blood-brain barrier. For this compound Bodor et designed an ingenious dihydropyridine-pyridinium salt type of redox delivery system. The active drug is administered as its 5,6-dihydropyridine derivative (Pro-2-PAM = b), which exists as a stable immonium salt c. The lipoidal b (pA"a = 6.32) easily penetrates the blood-brain barrier where it is oxidized to the active a. 

Generalizing the dihydropyridine pyridinium salt redox delivery system successfully applied to 2-PAM, Bodor et al. proposed an astute sustained release methodology for... 

The anodic oxidation of various dihydropyridine derivatives to the corresponding pyridinium or pyridine derivatives has been the subject of several investigations both in protic and aprotic solvents.229-237. The great interest in this process is because of the biological importance of the pyridinium-dihydropyridine redox system. 

The prepared compounds systematically differed in the distance of the dihydropyridine and the flavin recognition part. Binding between flavin and the NADH model systems was proved by potentiometric pH titrations. Redox reaction between the NADH model systems and flavin was monitored by UV - VIS spectroscopy. The intensity of the long-wave absorption of flavin at 456 nm significantly decreased during the reaction and the decrease was attributed to the reduction of flavin to the fully reduced flavohydroquinone. At the same time, the intensity of the peak around 360 nm decreased as well, because of the reduction of flavin and the concerted oxidation of the 1,4-dihydronicotinamide to the corresponding pyridinium species. Kinetics of the electron transfer was studied and two reasonable kinetic models were proposed. 

Heteroaromatic cations undergo reduction when treated with 1,4-dihydronicotinamide. An early study showed that the 10-methylacridinium ion (87) was rapidly reduced in a redox reaction to the 9,10-dihydro adduct by 1,4-dihydronicotinamides (M Scheme 18). A variety of systems including py-ridines, isoquinolines, quinolines and phenanthridines have been studied using this and related procedures. The selective reduction of pyridinium and quinolinium salts with 1-benzyl-1,2-dihydro-isonicotinamide (89) has been achieved. The selective conversion to the thermodynamically more stable 1,4-dihydro species (90 Scheme 18) is rationalized by the reversibility in the formation of the kinetic products (i.e. the 1,2-adducts) in the presence of pyridinium ions. In the pyridinium case 1,6-di-hydro adducts were also observed in some cases. Reactivity in such systems is sometimes hindered due to hydration of the dihydropyridine system. This is particularly so in aqueous systems designed to replicate biological activity. Dihydroazines derived from isoquinolines and 3,5-disubstituted pyridines have been reported to overcome some of these difficulties. ... 

A redox system (50/51) to affect brain delivery of y-aminobutyric acid (GABA) derivatives and analogues was also developed. Zincke reaction of 41 with acetal 49 followed by dithionite reduction afforded the 1,4-dihydropyridine prodrug 50, which was hydrolyzed and oxidized in vivo to the active GABA analogue 51. The neutral and lipophilic 1,4-dihydropyridine 50 can penetrate the blood-brain barrier (BBB), whereas the oxidized pyridinium salt 51 is retained in the brain for an extended period and then eliminated. 

In the oxidation of a substrate, the pyridinium cation in the oxidized form of the coenzyme accepts two electrons and one proton to be reduced to the corresponding 1,4-dihydropyridine which reduces the substrate in the reverse reaction. The stoichiometry of the redox reaction is depicted in Scheme 1, where SH2 and S indicate the... 

Rand, K.H. Bodor, N. el Koussi, AA. Raad, I. Miyake, A. Houck, H. Gildersleeve, N. Potential treatment of herpes simplex virus encephalitis by brain-specific delivery of trifluorothymidine using a dihydropyridine in equilibrium pyridinium salt type redox delivery system, J.Med.Virol., 1986, 20, 1-8. 

Lessons from Redox-Active Pyridinium Salts in Nature Nicotinamide Adenine Dinucleotide, Dihydropyridines, and Synthesis... 

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