Cyclic Amidine Research Articles

Unresolved rearrangement of thiazoline form of glutathione

The thiazoline form of glutathione was investigated with regard to its unresolved instability under neutral conditions. A simple method was developed for production of the thiazoline in stable solid form, thereby facilitating preparation of its neutral solution without using excess base and enabling isolation of the reaction product in quantity by ion-exchange chromatography. Analysis of the product by HPLC, infrared and ultraviolet absorption spectroscopy, mass spectrometry and proton magnetic resonance led to the identification of a cyclic amidine form of glutathione. The instability of the thiazoline is, therefore, due to an intramolecular rearrangement reaction, rather than hydrolysis. Once formed, the amidine is stable at pH 5-7 and in concentrated HCl, showing no tendency to rearrange back to either the original thiazoline or glutathione under these conditions.

Bacterial siderophores: structures of pyoverdins Pt, siderophores of Pseudomonas tolaasii NCPPB 2192, and pyoverdins Pf, siderophores of Pseudomonas fluorescens CCM 2798. Identification of an unusual natural amino acid

Pyoverdins were isolated and characterized respectively from the cultures of Pseudomonas tolaasii NCPPB 2192 (pyoverdins Pt, Pt A, and Pt B) and Pseudomonas fluorescens CCM 2798 (Pyoverdins Pf/1, Pf/2, Pf, Pf/3/1, and Pf/3/2) each grown in iron-deficient conditions. Their structures were established by using FAB-MS, NMR, and CD techniques. These siderophores are chromopeptides, and all but one (pyoverdin Pf/3/3) possess at the N-terminal end of their peptide chain the same chromophore that has been reported in pyoverdin Pa from Pseudomonas aeruginosa ATCC 15692 [Wendenbaum, S., Demange, P., Dell, A., Meyer, J. M., & Abdallah, M. A. (1983) Tetrahedron Lett. 24, 4877-4880] and pseudobactin B 10 from Pseudomonas B10 [Teintze, M., Hossain, M. B., Barnes, C. L., Leong, J., & Van der Helm, D. (1981) Biochemistry 20, 6446-6457] which is derived from 2,3-diamino-6,7-dihydroxyquinoline. In pyoverdins Pt this chromophore is bound to a linear peptide chain D-Ser-L-Lys-L-Ser-D-Ser-L-Thr-D-Ser-L-OHOrn-L-Thr-D-Ser-D-OHOrn (cyclic) which has its C-terminal end blocked by cyclic D-N delta-hydroxyornithine. In pyoverdins Pf, the peptide chain is also linear, SerCTHPMD-Gly-L-Ser-D-threo-OHAsp-L-Ala-Gly-D-Ala-Gly-L-O HOrn(cyclic), and contains an unusual natural amino acid which is the result of the condensation of 1 mol of serine and 1 mol of 2,4-diaminobutyric acid, forming a cyclic amidine. The pyoverdins Pt differ only in substituent bound to the nitrogen on C-3 of the chromophore, which is succinic acid in pyoverdin Pt A, succinamide in pyoverdin Pt, and alpha-ketoglutaric acid bound to the chromophore by its C-5 carbon atom in pyoverdin Pt B. Similarly, pyoverdin Pf/1, pyoverdin Pf/2, pyoverdin Pf (the major compound), and pyoverdin Pf/3/2 are substituted respectively by L-malic acid, succinic acid, L-malic amide, and succinamide. Pyoverdin Pf/3/3 has the same chromophore as azotobactin, the peptidic siderophore of Azotobacter vinelandii. These pyoverdins are very similar to pseudobactin B 10, the siderophore of Pseudomonas B10: they are linear peptides containing three bidentate groups strongly chelating Fe(III) and blocked at their N-terminal end by the catecholic chromophore and at their C-terminal end by cyclic N delta-hydroxyornithine. They differ therefore from other pyoverdins such as those from P. aeruginosa ATCC 15692 which contain a partly cyclic peptide [Briskot, G., Taraz, K., & Budzikiewicz, H. (1989) Liebigs Ann. Chem., 375-384].

S-[2-[(2'-carbamoylethyl)amino]ethyl] phosphorothioate and related compounds as potential antiradiation agents

A reinvestigation of the radiation protection activity of S-[2-[(2'-carbamylethyl)amino]ethyl] lithium hydrogen phosphorothioate (4a) revealed that this compound possessed good (70% protection at a dose of 600 mg/kg) activity. The thione and imino bioisosteres of 4, S-[2-(2'-thiocarbamylethylamino)ethyl] lithium hydrogen phosphorothioate (13a) and S-[2-(2'-amidinoethylamino)ethyl] phosphorothioic acid (18b) showed 100% protection at doses of 300 and 150 mg/kg, respectively. The N-methyl (4b) and tert-butyl (4c) analogues of amide 4a, the N-methyl (13b) analogue of the thioamide 13a, the N-methyl (18a) analogue of amidine (18b), and the cyclic amidine S-[2-[[2'-(4,5-dihydroimidozoyl)ethyl]amino]ethyl] lithium hydrogen phosphorothioate (21) all showed 80% protection at the highest dose tested.

ChemInform Abstract: The Synthesis of Amidine Acetals as Intermediates for the Preparation of Naturally Occurring Cyclic Amidine Antibiotics.

AbstractAcrolein dimethyl acetal (I) undergoes 1,3‐dipolar cycloaddition reaction with the sulfonyl nitrile oxide (II), prepared from phenylsulfonylnitromethan, to form the isoxazoline (III).

The Synthesis of Amidine Acetals as Intermediates for the Preparation of Naturally Occurring Cyclic Amidine Antibiotics

Abstract Regioselective 1,3-dipolar cycloaddition of (phenylsulfonyl)nitrile oxide to acrolein dimethylacetal gave the isoxazole 3. Nucleophilic displacement of the phenylsulfonyl moiety followed by reductive N-O bond cleavage gave the amidine acetal 6.

Modification of the cysteamine side chain of thienamycin. III.

Thienamycin derivatives (4) having a cyclic amidine moiety at the C-2 position were prepared. The susceptibility to renal dehydropeptidase-1 and the antimicrobial activity of these compounds were determined. Their structure-activity relationships are also discussed.

Mass spectrometric studies of a modified active-site tetrapeptide from delta 5-3-ketosteroid isomerase of Pseudomonas testosteroni.

Examination of the product of affinity labeling of delta 5-3-ketosteroid isomerase (EC 5.3.3.1) of Pseudomonas testosteroni by the suicide substrate [7-3H]5,10-secoestr-5-yne-3,10,17-trione has demonstrated that the steroid becomes bound by an acid- and base-labile linkage to an active-site peptide representing residues 55-58 (H2N-Tyr-Ala-Asn-Ser-CO2H) of the primary structure (Penning, T. M., and Talalay, P. (1981) J. Biol. Chem. 256, 6851-6858). Upon release of the steroid by mild acid hydrolysis, the peptide is converted into a more basic structure while retaining its amino acid composition (as determined by conventional means). These findings were rationalized by postulating that the steroid is bound as an imido ester via the amide group of asparagine 57 and that the polypeptide backbone participates (via attack by nitrogen or oxygen) in the hydrolysis of this ester with the formation of a cyclic amidine or basic oxazine. By comparing the properties of the isolated tetrapeptide, from which the steroid has been removed, with those of synthetic H2N-Tyr-Ala-Asn-Ser-CO2H and H2N-Tyr-Ala-Asp-Ser-CO2H by electron impact and fast atom bombardment mass spectrometry, we now have evidence for the presence of an oxazine (5,6-dihydro-6-iminio-4H-1,3-oxazine) in the modified peptide. Our results draw attention to the hitherto unsuspected degree of nucleophilicity of the amide group of the side chain of asparagine and the participation of this group in the formation of an imido ester.

Cyclic amidine inhibitors of indolamine N-methyltransferase

Syntheses of a large number of mono- and bicyclic, as well as a few tricyclic, amidine derivatives related to 2,3,4,6,7,8,-hexahydropyrrolo[1,2-a]pyrimidine (DBN) are reported. In vitro potencies for inhibition of the enzyme indolamine N-methyltransferase (INMT) from rabbit and human lung are presented. Four bicyclic amidine derivatives and 11 monocyclic derivatives were found to be equal or superior to DBN in in vitro potencies. With the bicyclic amidines, increasing ring size or introduction of substituents reduced activity. Among the monocyclic analogues, the most potent representatives were five- or six-membered systems with an exocyclic imino group, combined with methyl of ethyl substituents on the endocyclic nitrogen. Introduction of additonal substituents decreased inhibitory potency. 2,3,5,6-Tetrahydro-8H-imidazo[2,1-c][1,4]thiazine and 3-methyl-2-iminothiazolidine have been shown to cause inhibition of lung INMT when administered orally to rabbits.

Kinetic isotope effect in the reaction of 4-nitrophenylnitro-methane with the cyclic amidine base DBU [1,5-diazabicyclo(5,4,0)undec-5-ene

Kinetic deuterium isotope effects have been determined for the reaction of the cyclic amidine base DBU [1,5-diazabicyclo(5,4,0)undec-5-ene] with the carbon acid 4-nitrophenylnitromethane in toluene solution from –5 to +25°C. The isotopic rate ratio for the forward reaction (kHf/kDf) at 25°C is 13.3 ± 1.2; this is large enough to suggest an appreciable tunnelling correction. The activation enthalpies are strikingly low, both for proton and deuteron transfer: ΔH‡Hf= 2.0 ± 0.2 kcal mol–1(8.4 ± 0.8 kJ mol–1) and ΔH‡Df= 3.6 ± 0.3 kcal mol–1(15.1 ± 1.3 kJ mol–1). The interpretation of these results is discussed.

Die photochemische Tautomerisation eines cyclischen Amidins

AbstractThe cyclic amidine group of the 8‐amino‐2,3,5,5a‐tetrahydro‐5,8a‐propeno‐6H,11H‐pyrrolo[3,4‐g]‐1‐pyrindine (2) undergoes photochemical tautomerism. In this reaction the dihydropyridine group of a second molecule of 2 acts as a sensitizer.

Valence Tautomerism of Singly Protonated 9-Aminoacridine and its Implications for Intercalative Interactions with Nucleic Acids

Electronic absorption and fluorescence spectroscopy were used to show that the singly protonated 9-aminoacridine cation exists as the vinylogous cyclic amidine valence tautomer, the 9-iminoacridan monocation, in ground and excited states when in aqueous solution at physiological pH. The evidence indicates that the 9-aminoacridine monocation may intercalate into double-helical DNA in an orientation different from that employed by other acridine derivatives.

Electronic spectra of 2-aminoquinoline and 4-aminoquinaldine. Evidence for the cyclic amidine structures of the singly protonated cations

Electronic spectra of 2-aminoquinoline and 4-aminoquinaldine. Evidence for the cyclic amidine structures of the singly protonated cations

Reaction of Triethyloxonium Fluoroborate with Acid Amide. I. Formation of Cyclic Amidine and Tetrahydropyrimidine

Because several series of compounds having amidine moieties that had been synthesized had a marked effect on influenza viruses in mice, iminoesterification by the reaction of amides with triethyloxonium fluoroborate was examined and cyclic amidines were obtained by the reaction of a lactam with triethyloxonium fluoroborate, followed by ammonolysis of resulting ethyl imidate with ammonia. Thus, five kinds of cyclic amidines and two compounds of cyclic amidines having a carboxamide moiety were obtained by this method. On the other hand, the reaction of 3-benzoylaminopropionamide with triethyloxonium fluoroborate afforded a cyclized compound, 2-phenyl-5, 6-dihydro-4 (3H)-pyrimidinone, identical with an authentic sample prepared by the method of Kametani. Thus four compounds of 2-substituted 5, 6-dihydro-4 (3H)-pyrimidinone were synthesized, but, 3-substituted benzoylaminopropionamide having a negative group on the phenyl ring did not afford any cyclized compound, but did 3-benzoylaminopropionimidate. It was considered from these results that ethylation of oxygen atom in the benzamide moiety might be essential for this cyclization.

6-(m-Amidinophenyldiazoamino)-4-amino-1,2-dimethylquinazolinium Chloride Hydrochloride : a New Drug active against Babesia canis

As part of a study of diamidines which has extended over many years, we have recently screened for trypanocidal and babesicidal activity a number of compounds in which one of the amidine groups has been replaced by a cyclic amidine group. One of the most active of these is 6-(m-amidinophenyldiazoamino)-4-amino-1,2-dimethylquinazolinium chloride hydrochloride1 : (M. and B. 4986) (I). This compound, which contains the m-amidinophenyldiazoamino linkage present in the very active trypanocidal drug, isometamidium2, has babesicidal properties and is markedly active against Babesia canis in dogs.