Richard Neidlein

Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats

Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.

Mild preparation of 1-benzyloxyiminoalkylphosphonic dichlorides: application to the synthesis of cyclic phosphonic diesters and cyclic monoester amides

1-Benzyloxyiminophosphonates (3) were converted under very mild conditions to the corresponding phosphonyl dichlorides (5). The application toward the synthesis of diastereomeric 1,3,2,-oxazaphospholidines (6/7), and diastereomeric 1,3,2-dioxaphosphorinanes (8/9) is reported. The structure of 9a was confirmed by X-ray analysis

21,23-Dithiaporphycene : the first aromatic sulfur-containing system with porphycene structure

Abstract A porphycene analogue where two nitrogen atoms have been replaced with sulfur has been prepared from 2-(2-thienyl)-1H-pyrrole. Its X-ray crystallographic data, UV/VIS and NMR spectroscopic properties proved the 18 π electrons aromaticity of the system, like porphycene.

Synthese und Röntgenstrukturanalyse des Phenanthro[9,10-c]-1,2,5-telluradiazols / Synthesis and X-Ray Structure Analysis of Phenanthro[9,10-c]-1,2,5-telluradiazole

Abstract The synthesis of 1 by reaction of phenanthro[9,10-c]-1,2,5-selenadiazole with ethylmagnesium-bromide and TeCI4 is described; the X-ray structure analysis is reported.

The Syntheses of Heterocyclic Compounds with 1,2,4-Oxadiazole-as well as 1,2-Pyrazole-Rings

Abstract A variety of heterocyclic compounds have been prepared by the reaction of dicyanoketene ethylene acetal (3) with 1,3-dipolar reagents arenecarbonitrile oxides (2) and further reactions with hydrazine and its derivatives.

Ein Beitrag zum Tetrathiaporphycen-Redoxsystem: Elektrochemische Reduktion eines 20π-Cyclophans zum diatropen 22π-Dianion

SummaryThe reductive carbonyl coupling (McMurry reaction) of 5,5′-diformyl-2,2′-bithiophene affords the fourfold sulfur bridged [20]annulene5 and its [30]annulene homologue10 in 8 and 3% yields. Coupling of 5,5″-diformyl-2,2′:5′,2″-terthiophene produces structurally related macrocycles, albeit in very low yields. As shown by X-ray crystallographic investigation, the bridged annulenes5 and10 are non-planar cyclophanes exhibiting transannular electronic interaction. The sulfur bridged [20] annulene5 constitutes the central molecule of the tetrathiaporphycene redox system emcompassing the dicationic tetrathiaporphycene3, the annulene5, the 22π dianion8 and the two intermediate radical ion species. Compound5 is reduced in one two-electron step giving the diatropic 22-π dianion8 which is characterized by cyclovoltammetry, coulometry, spectroelectrochemistry and1H-NMR spectroscopy. By contrast,5 fails to undergo oxidation with formation of the dicationic 18π tetrathioporphycene.

Diarylsulfonamides as selective, non-peptidic thrombin inhibitors

Based on the structures of aminopyridine thrombin inhibitors (1), a series of aminoalkyl- and guanidinoalkyl-substituted diarylsulfonamides were prepared. The most potent derivative, N-[3-(4-guanidinobutoxy)-5-methyl-phenyl]-benzenesulfonamide (6c) had Ki = 0.18 microM for thrombin and did not inhibit trypsin, plasmin, or factor Xa. Comparison of the X-ray structures of the thrombin/1b and the thrombin/6c complexes revealed important aspects which govern the binding of such diarylsulfonamides to thrombin.

ω-Substituted alkyl carboxylic acids as antidiabetic and lipid-lowering agents

In screening experiments certain ω-substituted alkyl carboxylic acids, were found to produce an increase in insulin-stimulated 14C-acetate incorporation into triglycerides, which may indicate an improvement in the action of insulin. Antidiabetic and lipid-lowering properties in genetically diabetic ob/ob mice demonstrated the in vivo relevance of the insulin-potentiating effects seen in vitro. The chemical structures of the ω-substituted alkyl carboxylic acids with insulin-potentiating effects correspond to the general formula ring-spacer-COOH. A close structure-activity relationship was observed. The most potent compound in ob/ob mice was 3e, which normalized blood glucose as well as hyperinsulinaemia and lowered serum triglycerides and cholesterol by 52% and 37%, respectively. On the basis of these results, ω-substituted alkyl carboxylic acids are interesting as a new class of oral antidiabetic agents with insulin-sensitizing and lipid-lowering activity.

Physicochemical parameters involved in the lethal toxicity of N,N-[(dimethylamino)ethyl]-4-substituted benzoate hydrochlorides : a QSAR study

Summary A set of sixteen para -substituted N,N -[(dimethylamino)ethyl] benzoate hydrochlorides structurally related to procaine was synthesized. The apparent partition coefficients were determined by either shake-flask or HPLC methods and were taken as hydrophobic parameters. The IR stretching frequencies of the carbonyl group were determined in chloroform and taken as one of the electronic parameters. Additional physicochemical parameters were either taken from the literature: π, σ, ℑ and ℜ, MR 4 , or calculated: log P . The lethal potency was determined in the mouse via the LD 50 . In order to verify the nature and the relative contributions of the physicochemical parameters to lethal toxicity, QSAR equations were derived using regression analysis. A major contribution of hydrophobicity together with a smaller but still significant contribution of electronic or polar properties was found to describe the toxicity within this set of compounds.

21,23-Dithia-3,13-diazaporphycenes − Novel Aromatic Porphycene Analogues Incorporating Thiazole

The syntheses of the first examples of aromatic thiazole-containing porphycene analogues 3 have been accomplished by oxidation of the corresponding 3,20:10,13-diepithio-6,9:16,19-diimino-1,11-diaza[20]annulenes 9 with DDQ. Compounds 9a−c have been synthesized by McMurry coupling reaction of the diformylated 2-(1H-pyrrol-2-yl)thiazoles 8a−c, readily available by a three-step reaction sequence using 2-pyrrolethiocarboxamide (4) as starting material. The aromaticity of the 21,23-dithia-3,13-diazaporphycenes 3 is clearly established by NMR and UV/Vis spectroscopy and verified by X-ray crystal structure analysis of 3b.