Menadione, complexes

Vitamin K3 (menadione) complexed with polycyclic hydrocarbons (e.g., pyrenes) was investigated by Laskowski using a mixed fusion method [129]. Similar 1 1 complexes exhibited intensification of color upon cooling. These complexes have small association constants [130], and their small, sometimes even positive enthalpies of dissociation are probably due to contact charge transfer in the melt because the colors disappear on solidification of the products, probably due to loss of favorable orientation of the interacting components [1,131]. 

In addition to its industrial importance as an intermediate in the synthesis of vitamin K, menadione, or more specifically, salts of its bisulfite adduct, are important commodities in the feed industry and are used as stabilized forms in this appHcation. Commercially significant forms are menadione dimethyl pyrimidinol (MPB) (10) and menadione sodium bisulfite (MSB) (11). MSB is sold primarily as its sodium bisulfite complex. The influence of feed processing, ie, pelleting, on the stabiUty of these forms has been investigated (68). The biological availabiUties and stabiUty of these commercial sources has been deterrnined (69,70). 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Previous studies by Sorokin with iron phthalocyanine catalysts made use of oxone in the oxidation of 2,3,6-trimethylphenol [134]. Here, 4 equiv. KHSO5 were necessary to achieve full conversion. Otherwise, a hexamethyl-biphenol is observed as minor side-product. Covalently supported iron phthalocyanine complexes also showed activity in the oxidation of phenols bearing functional groups (alcohols, double bonds, benzylic, and allylic positions) [135]. Besides, silica-supported iron phthalocyanine catalysts were reported in the synthesis of menadione [136]. 

Proceeding along a parallel track, Guillory and coworkers used DTA analysis to study complexation phenomena [2]. Through the performance of carefully designed studies, they were able to prove the existence of association complexes and deduced the stoichiometries of these. In this particular work, phase diagrams were developed for 2 1 deoxycholic acid-menadione, 1 1 quinine-phenobarbital, 2 1 theophylline-phenobarbital, 1 1 caffeine-phenobar-bital, and 1 1 atropine-phenobarbital. The method was also used to prove that no complexes were formed between phenobarbital and aspirin, phenacetin, diphenylhydantoin, and acetaminophen. 

S.3 Cytochrome P450 Model Compounds Functional. Ferric-peroxo species are part of the cytochrome P450 catalytic cycle as discussed previously in Section 7.4.4. For instance, these ferric-peroxo moieties are known to act as nucleophiles attacking aldehydic carbon atoms in oxidative deformylations to produce aromatic species.An example of this work, establishing the nucleophilic nature of [(porphyrin)Fe (02)] complexes, was achieved for alkene epoxidation reactions by J. S. Valentine and co-workers. The electron-deficient compound menadione (see Figure 7.18) yielded menadione epoxide when reacted with a [(porphyrin)Fe X02)] complex. 

Photooxidation of Ade by menadione results in a complex sequence of reactions to a formylation and acetylation of Ade at N( 6) (Wang and Liu 2002). These groups stem from the sensitizer. 

Several inherited disorders are associated with faulty operation of the electron transport pathway. ATP production is diminished in such cases. These disorders are known as mitochondrial myopathies, and they are associated with the absence of specific polypeptide chains found in complexes I, III, or IV. In many cases, the problem may be traced to specific lesions in mitochondrial DNA, which codes for at least 13 polypeptide chains found in these complexes. Myopathies are tissue specific some affect the heart, others the skeletal muscle. Many are accompanied by lactic acidosis, because the inability to reduce NADH normally results in its accumulation and the channeling of pyruvate toward lactic acid production. In complex I disorders, the oxidation of FADH2 is not impeded. In complex III lesions, neither NADH nor FADH2 can be oxidized. However, use has been made by B. Chance and colleagues of menadione (Chapter 6) and ascorbic acid in such cases. The former can oxidize UQH2, whereas ascorbate can oxidize menadione and reduce cytochrome c. Marked clinical improvement in affected patients follows such treatment. 

Menadione (vitamin K3),phylloquinone (vitamin Kj), and ascorbate (vitamin C) have been used to donate electrons to cytochrome c. For example, ascorbate is oxidized to dehydroascorbate as it uses its electrons to reduce cytochrome c directly. The dehydroascorbate is quickly reduced to ascorbate in the mitochondrion by NADH or FADH2. Menadione appears to improve cellular phosphate metabolism and to enhance electron transfer after a respiratory Complex I block. 

Fia. 5. Kinetics of the resolution of complex I as a function of temperature of the incubation medium. The release of menadione reductase activity was measured as an index of resolution 2 min after incubation of complex I with 0.47 Af NaC10< at the temperatures indicated. From Davis and Hatefi (69). 

Complexes formed as a result of interaction between the drugs and pharmacologically inert substances can enhance the photostability of the drugs. Kowarski and Ghandi (126) found that the presence of the quaternary ammonium compound, cetylethylmor-pholinium ethosulfate,in solutions of menadione slowed the rate of photodegradation caused by exposure to 253.7nm UV radiation. This effect was attributed to complex formation between menadione and the quaternary ammonium compound. 

Several electron donors form molecular complexes with menadione, which then suppress its photodecomposition in aqueous solutions (107). DNA-daunomycin complexes exposed to UV irradiation are reported by Gray and Philips (127) to be more stable than daunomycin alone. The photostability of nifedipine increases on the addition of PVP (64,128). However, the rate of photobleaching of riboflavin by VIS radiation is considerably enhanced by PVP (28). 

Kowarski CR, Ghandi HI. Complex formation between menadione and cetylethylmor-pholinium ethosulfate effect of UV photodegradation of menadions. J Pharm Sci 1975 64(4) 696-698. 

The low molecular weight (Type II) NADH dehydrogenase is a subcomplex of the former [283,284], and may be prepared from Complex I by treatment with chao-tropic agents [285]. Type II dehydrogenase catalyses oxidation of NADH by several acceptors such as cytochrome c, ubiquinone-1 and menadione. It contains approx, four non-haem Fe and four acid-labile S/FMN, and has a molecular weight between 70 and 80000. 

Hetrogai iL [Heterochem] Menadione sodium bisulfite complex. 

Fig. 9. Charge-transfer band of complexes of 3,5-diiodotyrosine and 3,5-dibromotyrosine with menadione. Use of phenolate and menadione alone gave no absorption in this region. Dotted line indicates anticipated featureless band. (From ref. 18)...

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