M. Poje

The mechanism for the conversion of uric acid into allantoin and dehydro-allantoin : A new look at an old problem

Abstract The reaction of uric acids 1 with iodine in alkaline solution yields, on acidification, new dehydro-allantoins 11, or normal oxidation products, allantoins 13, depending on whether an excess or a stoichiometric amount of oxidant was used. The structure and regiochemistry of dehydro-allantoins 11 was established by chemical, spectroscopic, and 14C-labelling methods. These experimental results, in combination with other data, generate a new mechanistic scheme for the uricolytic pathway to allantoin, ruling out the intervention of a symmetrical transition state prior to the decarboxylation step.

Tracing and identification of uricase. Reaction intermediates.: A direct 13C-NMR/isotope-labelling evidence

Abstract The 13C-NMR spectra are characteristic and provide a convenient method to chart the pathway of uricase-catalysed oxidation of [5-13C]urate (1) to [4-13C]allantoin (5); 5-hydroxy[5-13C]isouric acid (2), its ring-opened derivative 3, and [4-13C]allantoin-5-carboxylate (4) were identified as consecutive intermediates in D2O/phosphate (pD 7.2).

The mechanism for the conversion of uric acid into uroxanate and allantoin: a new base-induced 1,2-carboxylate shift

Abstract Alkaline permanganate oxidation of uric acid (1), particularly the late stages of the transformation into uroxanate (7) and allantoin (3), was studied by means of isotope-position labelling. A clear-cut degradation procedure developed for distinguishing among carbonyl and α-aminal carbon atoms in these products demonstrated conclusively that the carboxylic carbon of 7 and the 4-carbonyl carbon of 3 have their origin in C(5) of uric acid (1). None of the mechanisms that have been proposed for this reaction would have predicted this result. Isotope-labelling evidence, in combination with other data, revealed the sequence of events and identities of species involved in oxidative transformation of 1 ; the carbon-skeleton rearrangement of the first transient intermediate 4 must occur by a 1,2-carboxylate shift to give allantoin-5-carboxylate (6) which either decarboxylates to allantoin (3) or else undergoes hydrolytic ring opening to uroxanate (7).

The stereostructure of trimers of biacetyl

Abstract Structures of two trimers of biacetyl were determined on the basis of chemical and spectroscopic evidence and the single-crystal X-ray analysis. The compounds are shown to be exo-3, endo-7-diacetyl-1- hydroxy-endo-3,5,exo-7-trimethyl-cis-2,4,6-trioxabicyclo[3.3.0]octanc (2) and 11-hydroxy-1,3,5,7,11- pentamethyl-cis-2,4,6,8-tetraoxatricyclo[3.3.3.03.7]undecan-9-one(3).

Structure-activity relationships of alloxan-like compounds derived from uric acid.

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.

Synthesis and structure of dehydro-4-iminoallantoin and its covalent adducts

Abstract Representations of two consecutive products of the Denicke reaction were shown to be incorrect. Oxidation of uric acid (1a) by ferricyanide in aqueous ammonia gives 5-amino-4-iminoallantoin (4) and 1,5-diamino-3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]octane (5a), while methylated uric acids 1b-g afford only the corresponding end products 5. The key dehydro-4-iminoallantoin (6) arose on exposure of the primary adduct 4 to dilute acetic acid; a direct route to 6 was provided by oxidation of 1-iminoallantoin (2) with iodine. Both dehydro-allantoin (8) and its 4-imino analogue 6 form covalent adducts (e.g. with MeOH) at the 5-position. A brief rationale which focusses upon the stepwise nature and regiochemical course of the reaction is presented.

New cyclic aminimides containing pyrazolone skeleton

Abstract The synthetic route to 1,1-dimethylpyrazolin-5-on-1,2-aminimides ( 2 ), is described, involving the cyclization of diethyl acylmalonates ( 1 ) with 1,1-dimethylhydrazine.

Diabetogenic action of alloxan-like compounds: The effect of dehydrouramil hydrate hydrochloride on isolated islets of langerhans of the rat

SummaryDehydrouramil hydrate hydrochloride (DHU) is an analogue of alloxan which retains the in vivo diabetogenic activity of alloxan but, in contrast to alloxan, is stable in aqueous media at physiological pH. Using rat islets of Langerhans, we have studied the acute effects of DHU on B cell function. Glucose-stimulated insulin release was markedly inhibited by DHU, the concentration of DHU giving 50% inhibition (I50) was 1 mmol/l; this was lowered to 0.5 mmol/1 when the islets were exposed to DHU for 5 min before elevation of glucose concentration. The basis for this change appeared to be a protective effect of glucose, since the inclusion of 3-0-methylglucose during pre-incubation with DHU also attenuated the subsequent inhibition of glucose-stimulated insulin release. The inhibitory effect on glucose-stimulated insulin release of a 5-min exposure to DHU persisted throughout a subsequent 120-min period in the absence of DHU. DHU also inhibited insulin release stimulated by mannose (20 mmol/l) or by 2-ketoisocaproate (20 mmol/l) with I50 of 1 and 0.5 mmol/l respectively. Concentrations of DHU up to 1 mmol/l had no significant effect on islet glucose oxidation or ATP content; 5 mmol/l DHU did not affect the rate of glucose oxidation, but lowered the ATP content by 30% without pre-incubation and by 60% in islets pre-incubated for 5 min with DHU before addition of glucose. Inhibitory effects of DHU were also found on rates of incorporation of [3H]-leucine into insulin plus proinsulin and into total islet protein; however, these parameters were less sensitive to DHU than was insulin release. These effects of DHU were similar to those of alloxan. These data suggest that DHU is an important new tool for studying the mechanism of action of B cell cytotoxic agents; in addition, the fact that DHU is a potential metabolite of uric acid could have relevance to the aetiology of diabetes mellitus.

Structural revision of uric acid glycol half-ethers

Abstract The classic formulae of uric acid glycol half-ethers (2) are revised; compounds with R1=H are shown to have 3,4-ring-opened structures 4 while those with R1=R3=Mc,R7=H are 1-carbamido-5-methoxy-alloxanic acid amides (5), derived by a further rearrangement, possibly involving the l,3a,5-triazapentalene related transition state.

Key intermediates in the caffolide pathway for degradation of uric acid. X-ray structure of methylammonium 1-methylcaffolide

Abstract Alloxanic acid ureides ( 3 ) formed by oxidative ring fission at the 3,4-bond of uric acids ( 1 ), undergo a facile rearrangement to isomeric products whose ammonium caffolide structure 5 was established by synthesis and confirmed by X-ray analysis of methylamine salt of 1-methylcaffolide ( 5b ).