l-Cystine Diamides as l-Cystine Crystallization Inhibitors for Cystinuria.

l-Cystine bismorpholide (1a) and l-cystine bis(N'-methylpiperazide) (1b) were seven and twenty-four times more effective than l-cystine dimethyl ester (CDME) in increasing the metastable supersaturation range of l-cystine, respectively, effectively inhibiting l-cystine crystallization. This behavior can be attributed to inhibition of crystal growth at microscopic length scale, as revealed by atomic force microscopy. Both 1a and 1b are more stable than CDME, and 1b was effective in vivo in a knockout mouse model of cystinuria.

Synthesis, gastroprotective effect and cytotoxicity of new amino acid diterpene monoamides and diamides.

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.

Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents.

This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.

Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat.

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.

[The influence of diamide on the realization of the radioprotective effect of beta-mercaptoethylamine in the postradiation period]. / Vliianie diamida na realizatsiiu radiozashchitnogo éffekta beta-merkaptoétilamina v postradiatsionnom periode.

In the experiments with Ehrlich ascites tumor cells it was shown that specific oxidation of cellular glutathione after irradiation produced no effect on the degree of radiation injury in the air, but resulted in a decrease of radioprotective effect of beta-mercaptoethylamine. From these results it follows that for a complete realization of radioprotective effect normal level of cellular glutathione is necessary.

Application of non-hypoxic cell sensitizers in radiobiology and radiotherapy: rationale and future prospects.

The effects of commonly used non-hypoxic cell radiosensitizers are briefly reviewed. Emphasis is placed on the effects and the mechanism of action of halogenated pyrimidines, since recent clinical trials indicated the potential importance of these compounds in the treatment of certain types of human tumors. Evidence is presented suggesting that halogenated pyrimidines sensitize cells to radiation by increasing induction of DNA and chromosome damage per cell per unit absorbed dose, as well as by increasing the susceptibility to fixation of radiation induced PLD. The former mode of action correlates with an increase in survival curve slope, whereas the latter probably causes the reduction observed in shoulder width. The effects of repair inhibitors such as the nucleoside analogs are briefly reviewed and their possible clinical importance discussed. Results are presented indicating that combined treatment with halogenated pyrimidines and nucleoside analogs may enhance the radiosensitizing effect of the former and the specificity on tumor cells of the latter. Finally, the effects of other radiation sensitizers such as 3-aminobenzamide and diamide are briefly summarized.

The use of non-hypoxic cell sensitizers in radiobiology and radiotherapy.

Many different non-hypoxic cell radiosensitizers have been identified over the years. Radiosensitization by these agents is mediated through a variety of mechanisms, including inhibition of repair (both enzymatic and chemical), modification in the DNA molecule, and perturbation and redistribution in the cell cycle. Recent clinical interest in the use of halogenated pyrimidines as radiosensitizers has prompted a number of questions requiring both laboratory and clinical research to maximize this therapeutic approach. Other radiosensitizers that alter cellular redox processes in different ways are discussed in the context of better understanding the cellular biochemical systems that are affected in aerobic radiosensitization. Advancement in the use of non-hypoxic cell sensitizers in radiation cancer treatment will most likely depend on a knowledge of the detailed biochemical mechanisms of these agents and how they might be used to exploit any subtle biochemical differences between tumor and normal tissue.

[Contribution to the problem of preventing recurrences of oxalate and phosphate urinary caluli: active modification of citrate excretion and Ca++-binding capacity in the urine of Wistar rats]. / Beitrag zum Problem der Rezidivprophylaxe von Oxalat- und Phosphatharnsteinen: Aktive Beeinflussung der Zitratausschidung und der Ca++-bindungs-kapazität im Harn bei Wistarratten.

Citric acid may well be, quantitatively and in terms of complex chemistry, the most important of the organic acids capable of binding Ca++ in urine. Since the quantitative determination of citrates in urine became a routine method in many research-orientated urological laboratories thanks to the introduction of standardized enzymatic tests, reports of a reduced excretion of citrates in patients with (recurrent) (oxalate) calculi have become frequent. During our long-term study of patients with recurrent formation of calculi we also observed a clear deficit of citrates in their morning, midday and evening urine. The conspicuous incidence of calculi when there is a concurrence of hypocitraturia and alkaline urine (RTA, in animal experiments: acetazolamide) clearly suggests the lithoprotective significance of citric acid. By quantitatively testing a large number of organic compounds which are interesting both structurally and in terms of complex chemistry, it has been possible to find some substances which restrict crystallization, raise the level of citrates and bind Ca++. A few have also found to restrict the excretion of oxalate in Wistar rats.