Reevaluation of products derived from 3,9-dimethyluric acid in a chlorination−reductive dechlorinaton sequence has demonstrated unequivocally that they are not purines. Spectroscopic and degradative ...evidence, in conjunction with position-labeling NMR studies, revealed an unprecedented oxidative ring transformation pathway involving the key purine-to-imidazo1,5-cimidazole rearrangement.
The scheme shows the binding of uric acid (
1a) to the critical Arg residue; its equivalent
2a (R
=
H) did not affect insulin release.
Uric acid (
1a) suppresses basal insulin release in isolated rat ...pancreatic islets and inhibition of glucose-stimulated insulin secretion (GSIS) occurs right at hyperuricaemic levels (⩾0.4
mM). Conversely, 1
mM guanidinium urate (
2a) was completely ineffective, strongly suggesting that binding to an essential arginine residue triggers the inhibitory effect. A specific recognition of
1a molecule at the crucial β-cell receptor is probably involved in the blocking glucose signal transduction.
Divergent acid‐catalysed ring‐openings of 4,5‐dimethoxytetrahydropurine‐2,6,8‐triones 2 at position 4, yielding 1‐(5‐methoxyhydantoin‐5‐carbonyl)ureas 4 (R7 = Me) or ...5‐methoxy‐5‐ureido‐2,4,6‐pyrimidinetriones 5 (R7 = H), can be rationalized by assuming a preference for one of two conformational isomers of the cis‐fused system, associated with the N‐substitution effects. Intramolecular transamidation 5 → 4 presumably occurs via a bicyclic acid aminal type intermediate 3, heretofore misassigned as the reaction product. A curious base‐catalysed rearrangement was encountered with the 5 (R1 = R3 = Me, R7 = H) cases, which afforded 5‐methoxy‐1,5‐bis(methylaminocarbonyl)hydantoins 7. Remarkable stability of the conformationally rigid propellane type 4,5‐ethylenedioxytetrahydropurine‐2,6,8‐triones 9 toward acids, shows that the mode of ring‐opening at position 4 is controlled by powerful Stereoelectronic factors. However, an alternative ring‐opening at the 1,6‐bond has occurred on heating aqueous solutions of 9a (R7 = H); the ensuing decarboxylative rearrangement leads to 1,3‐dimethylallantoin (12) and its precursor, 1‐(2‐hydroxyethoxy)‐2,4‐dimethyl‐3,7‐dioxo‐2,4,6,8‐tetraazabicyclo3.3.0octane(11).
1
The diabetogenic activity of a range of alloxan‐like compounds derived from uric acid has been investigated.
2
The classes of derivatives were: 5‐substituted‐isouric acids; 4,5‐disubstituted‐4, ...5‐dihydrouric acids; 5‐substituted‐pseudouric acids; salts of dehydro‐uramil hydrate; salts of dehydro‐isouramil hydrate; alloxan derivatives.
3
Compounds were tested by intravenous injection into rats and diabetogenic activity assessed by production of persistent hyperglycaemia and glycosuria.
4
The only essential structural feature common to all active compounds was the presence of a quinonoid pyrimidine system or its hydrated equivalent. The presence of the five‐membered ring of uric acid (or an opened form thereof) did not abolish and in some compounds enhanced diabetogenic activity.
Three synthetic routes to salts of 5-amino-5-hydroxy-2,4,6(1H,3H,5H)-pyrimidinetrione (10) are described. The key reactions involved acid-catalyzed cleavage of ...5-amino-5-ureido-2,4,6(1H,3H,5H)-pyrimidinetrione (7), conversion of uramil (8) to dehydrouramil (9) and subsequent hydration, and the condensation of alloxan (5) with ammonium salts. The carbinol ammonium salt structure 10a was unambiguously established by X-ray crystallography. New alloxan-like compounds 7, 9, and 10 were evaluated for diabetogenic activity in rats. Compound 7 was inactive, whereas compounds 9 and 10 showed the highest activity comparable to that of streptozotocin (12).
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