Alloxan mechanism

Fig. 4. Mechanisms for decomposition of uric acid-4,S-diol to allantoin (V), alloxan (VI), urea (VII) parabanic acid (XIV) and COj...

Fig. 13. Proposed mechanism for formation of alloxans from the methylated uric acid-4,5-diol derived from theobromine and caffeine. Molar amounts of products are those formed in 1 M HOAc...

The unusual condensation between alloxan and o-amino-N,N-dimethylaniline yields the tetrahydroquinoxaline spiran 21.28 A possible mechanism for spiran formation involves the acid-promoted cyclization... 

Photoaddition of nucleophiles to heterocycles is often observed.1 Irradiation of acridine and its quaternary salt in ethanol produced 9,9 -bisacridan (151) as the major product besides a little acridan and 9a-hydroxyethylacridan.207 The reaction mechanism is most likely a hydrogen abstraction from the alcohol by the excited molecule, followed by competitive radical combination to yield 151. Irradiation of an aqueous solution of alloxan monohydrate and its derivatives produces an alloxantin-type dimer (152 R = H, Me, Et) by combination (at the 5-position) of a radical intermediate.208... 

Induction of hormesis and adaptive responses by low dose radiation have been extensively studied (Wang et al, 2008). Pre-exposure of diabetic prone mice to low dose radiation (LDR) has reduced the incidence of alloxan diabetes and delayed the onset of hyperglycemia, although the mechanisms are unclear (Wang et al, 2008). Low intensity laser (LIL) has stimulated healing in diabetes (Wang et al., 2008). 

Thus polyhydroxylated triterpenes from E. japonica are very active as hypoglycemic agents. Noreen and Villar (38,39) proposed that the crude alcoholic extract of E. japonica and tormentic acid act by stimulating Langerhan s p cells which results in an increased insulin release because the crude extract and tormentic acid are inactive in alloxan-treated animals. The action mechanism of S and 7 seems to be analogous. Studies are in progress to delineate this mechanism more precisely. 

The prototype reaction is the conversion of glyoxal into glycolic acid (equation 2), and here the benzilic acid rearrangement mechanism coincides with that for an intramolecular Cannizzaro reaction. The reaction is observed with other purely aliphatic a-diketones such as f-butyl 2,3-dioxobutyrate and cyclohexane-1,2-dione (equations 3 and 4), but the scope is limited in the aliphatic series by competing (c.g. aldol) reactions. Suitably constructed heterocyclic systems also rearrange, and the conversion of alloxan (3) into alloxanic acid (4) was among the first of the benzilic acid rearrangements to be discovered (equation 5). ... 

Mechanisms of nonenzymatic glycosylation in normal, senile, spontaneously diabetic, and chemically induced (alloxan and/or streptozotocin) diabetic animals have been intensively investigated (selected references, C3, D5, F16, H9( K16, S25, V6, W20, Y5). However, since the life span of proteins in experimental animals differs very appreciably from that of those in the human, their applicability should only be regarded in general terms. Where pertinent, such experimental studies have been discussed under the relevant sections. 

I. Mechanism of toxicity. PNU is believed to antagonize the actions of nicotinamide and, in a manner similar to that of alloxan and streptozocin, injure pancreatic beta cells. The mechanisms of autonomic neuropathy and central nervous system effects are unknown. Adrenergic neurons acting on blood vessels but not the heart are affected. As a result, orthostatic hypotension associated with an intact reflex tachycardia is the usual picture. 

Alloxan apparently also acts by interacting with SH groups and lowering the blood glutathione, since its action is prevented by SH-containing compounds such as glutathione, cysteine, BAL (2,3-dimercaptopropanol) or thioglycolic acid administered immediately before or within a few minutes after injection of alloxan [82, 86, 87]. However, the actual mechanism by which alloxan acts is still rather poorly understood. 

Pretreatment with alloxan, which induces a hyperglycemic state similar to that found in diabetic humans, also enhanced the hepatotoxic effects of 1,1,2-trichloroethane in rats as indicated by increased SGPT activity and increased hepatic triglyceride concentration (Hanasono et al. 1975). The mechanism of this interaction is unknown. 

Gao, D., Q. Li, Z. Liu, et al. 2007b. Hypoglycemic effects and mechanisms of action of Cortex Lycii Radicis on alloxan-induced diabetic mice. Yakugaku Zasshi 127(10) 1715-1721. 

Since isovioluric acid represents an unusual oxime of alloxan, it is not surprising to find that dilute hydrochloric add rearranges it to violuric acid. The simplest mechanism which suggests itself for this reaction involves two steps (1) the hydrolysis of isovioliuic add to alloxan and hydroxylamine, and (2) the recondensation of these to form violuric add. 

We have already shown that alloxan and streptozotocin induce islet DNA strand breaks and that poly(ADP-ribose) synthetase acts to repair the DNA breaks, consuming islet NAD [4-7]. This rapid and marked depletion of islet NAD has been regarded as the primary molecular mechanism behind the B-cell necrosis. The B-cells seem to be making a suicide response to repair the damaged DNA. Therefore, poly(ADP-ribose) synthetase inhibitors can prophylactically prevent alloxan and streptozotocin diabetes by blocking the NAD consumption (Fig. 4). 

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