Ilana Tamir

Oxidation of methyl derivatives of pteridin-4-one, lumazine and related pteridines by bovine milk xanthine oxidase

1. Pteridin-4-ones, methylated at nitrogen or carbon, N-methylated lumazines and related oxopteridines were studied as substrates of a highly purified bovine milk xanthine oxidase (xanthine : oxygen oxidoreductase, EC 1.2.3.2). 2. The enzyme can oxidise at high rates both uncharged and anionic substrates. Variation of enzymic activity with pH is mainly due to pH-dependent changes in the active enzymic center. 3. Milk xanthine oxidases at different stages of purification convert pteridin-4-one into the 4,7-dione (compound 13 in this article). 4. Methylation at C-6 in the pyrazine moiety enhances enzymic attack at C-2 in the pyrimidine ring. N-Methylation may increase or reduce rates of oxidation. 5. For oxidation at C-2, the most favorable form of the substrate bears a double bond at C(2) = N(3). Attack at C-7 is enhanced strongly in structures bearing a double bond at C(6) = C(7). 6. In general, pteridines react with xanthine oxidase as non-hydrated molecules. However, oxidation of 8-methyllumazine at C-7 may take place by dehydrogenation of the 7-CHOH group of the covalently hydrated molecule.

Conversion of ruscogenin into 1α- and 1β hydroxycholesterol derivatives : Structure elucidation by computer assisted analysis of their lanthanide-induced nmr shifts

Abstract The chemistry of ruscogenin (1) was studied since its structural features qualify it to serve as a potential starting material for 1-hydroxy vitamin D analogs. Ruscogenin was oxidized to the 1-oxo-derivative 2 which was reduced to a mixture of ruscogenin (1) and 1-epiruscogenin (3). Both 1 and 3 were converted by Clemmensen reduction to the respective tetrols 12 and 21, which were further reduced to the triols 15 and 25 and diols 16 and 24 by consecutive treatment with p- toluenesulfonyl chloride and LAH. The reduction of triol 15 to diol 20 was achieved by selective benzoylation of positions 1 and 3, and mesylation of position 16 followed by LAH reduction. The utility of the shift reagent Eu(dpm)3 to determine the structures of the products was studied. It was shown that the shifts induced are characteristic of the position and orientation of the OH groups, and can facilitate the elucidation of the structures of hydroxylated steroids.

A nuclear magnetic resonance study of hindered rotation in 8-phenylpurines

Abstract In the PMR spectrum of 8-phenylpurines, the multiplet of the o-protons appears downfield of the multiplet, characteristic for m,p-protons. The separation of the centres of these two signals (Δ-value) diminishes with increasing steric interference between the phenyl ring and substituents in the imidazole moiety. The contribution of the purine ring current to the chemical shifts of the aromatic protons was calculated according to the theory of Johnson and Bovey, and the torsion angles θ between the phenyl ring and the plane of the purine system were derived. For 8-phenylpurines with an NH-group in the imidazole ring, θ is 10–15°; for compounds with an N-methyl group in this ring, θ ≈ 35–45°; in 3,9-dimethyl derivatives, Δ becomes zero, while θ is about 50°.

Long-range spin-spin coupling between N-methyl and ring protons in some purines and pteridines

Abstract Long-range spin-spin coupling of ca. 0.5 Hz over four bonds between N -methyl and adjacent ring CH protons is observed for a wide variety of purines and pteridines. Factors which permit this coupling to be detected are discussed.

Reactivity of 6-methylthiopurin-8-ones. Properties of 6-methylsulphonylpurin-8-ones

All 6-methylthiopurin-8-ones (except those bearing a 1-methyl substituent, which decompose) are converted by chlorine in methanol at 0° into the corresponding sulphones. In a series of N-methyl 6-methylthiopurin-8-ones, only the 1-methyl, the 1,9- and 3,9-dimethyl, and the 3,7,9-trimethyl derivatives undergo thiohydrolysis. In contrast, all the corresponding sulphones are attacked by hydrogen sulphide anion. A 6-methylsulphonyl substituent weakens basicity and increases the acid strength of purines. In 6-methylsulphonylpurin-8-one, anion formation follows the order N-9 → N-7. A 3-methyl substituent, by virtue of reduction of the ring current in the pyrimidine system, causes a diamagnetic shift of the 2-H signal.

Interference between peri-substituents at positions 3 and 9 in purines and positions 1 and 8 in pteridines, shown by nuclear magnetic resonance spectroscopy. Proposal of a steric model

In purines, including uric acids, steric interference between 3- and 9-methyl substituents leads to a marked down-field shift of their n.m.r. signals, of 0.20–0.40 p.p.m. In 1,8-dimethylpteridine-2,4,7-triones, the displacement of the methyl bands is less marked (0.12–0.18 p.p.m.). Two models are discussed to explain these downfield shifts: either moving the methyl groups out-of-plane, or spreading them apart within the plane of the heterocyclic structure. Calculations show that only the latter model is in accordance with the measured values. The smaller change of the δ-values in pteridine-2,4,7-triones can be explained by the observation that in 1- or 8-monomethyl derivatives the 7,8-or 1,2-lactam group, respectively, is partially lactimised.

Interaction of Cannabinoids with Model Membranes — NMR Studies

In a attempt to clarify the mode of psychotropic action of Δ1-tetrahydrocunnabinol (Δ1-THC), a comparison was undertaken between its effects on the physical properties of model membranes and those of the psychotropically inactive cannabidiol (CBD). The two cannabinoids were incorporated into sonicated dispersions of mixtures of various relative compositions of egg yolk lecithine (EYL) and cholesterol.

Purine-6,8-diones: a study of their ionisation and their methylation reactions

Purine-6,8-diones are divided by their physical properties into three classes: those of class (a) carry a hydrogen atom or a methyl group at position 1, and those of class (b) bear a 3-methyl substituent. The members of class (c), bearing both 1- and 3-methyl groups, exist either as betaine or, after protonation, as the conjugate acids, with the positive charge confined to the pyrimidine ring. Anions are formed predominantly by proton loss from position 9. Consistent with this, methylation of monoanions proceeds at position 9, except in the case of members of class (b), where alkylation at N-9 is sterically hindered by the 3-methyl substituent. Methylation of dianions follows in general the sequence of proton attachment, unless steric factors prevent this.Protonation and alkylation of neutral molecules proceeds predominantly in the pyrimidine ring. However in the case of 9-methyl derivatives, methylation at N-3 is sterically hindered.