Antioxidative property of T-0970, a new ureidophenol derivative

We investigated the antioxidative property of T-0970, a newly synthesized ureidophenol derivative. The inhibitory effect of T-0970 on spontaneous lipid peroxidation in rat brain was 10 times greater than those of well-known antioxidants such as butylhydroxytoluene (BHT), probucol and α-tocopherol. T-0970 also showed dose-dependent free radical scavenging activities in vitro for both superoxide anions and hydroxyl radicals. The radical-scavenging potencies of T-0970 were about 10–30 times stronger than those of BHT. We evaluated the in vivo antioxidative ability of T-0970 in the animal model of acute oxidative tissue injury in rats. Intraperitoneal injection of ferric nitrilotriacetate (Fe/NTA) caused an acute and remarkable increase in the level of thiobarbituric acid-reactive substances (TBARS) in both plasma and the liver, and also resulted in a considerable elevation of the plasma levels of GOT and GPT indicative of hepatic injury. Both oral and intravenous administration of T-0970 dose-dependently depressed these diagnostic parameters. These results indicate that T-0970 may have a therapeutic potential in various diseases associated with oxidative tissue injury.     

Crystallization of a derivative of a new coenzyme,methoxatin

A new compound, derived from a parent compound to which we have given the trivial name, methoxatin, has been isolated from a methanol-oxidizing bacterium, and crystallized. Its chemical structure was determined by X-ray crystallography. Methoxatin is implicated as a coenzyme in the oxidation of substrate alcohols. This report describes the purification and crystallization of the derivative, acetonyl methoxatin.     

Thiazinogeldanamycin, a new geldanamycin derivative produced by Streptomyces hygroscopicus 17997

A new geldanamycin (GDM) derivative was discovered and isolated from the fermentation broth of Streptomyces hygroscopicus 17997. Its chemical structure was elucidated as thiazinogeldanamycin by LC-MS, sulfur analysis, and NMR. The addition of cysteine to the fermentation medium significantly stimulated the production level of thiazinogeldanamycin, suggesting cysteine as a precursor of thiazinogeldanamycin production. Although showing a decreased cytotoxicity against HepG2 cancer cells, thiazinogeldanamycin exhibited an improved water solubility and photostability. Thiazinogeldanamycin may represent the first natural GDM derivative characterized so far that uses GDM as its precursor. Its appearance also clearly indicates that an appropriate end-point of fermentation is of critical importance for the maximal production of GDM by Streptomyces hygroscopicus 17997.     

Talampicillin: a new derivative of ampicillin.

Talampicillin is a thiazolide carboxylic ester of ampicillin and is hydrolysed in the intestinal mucosa to release free ampicillin. The mean peak serum concentration of ampicillin occurred one hour after a dose of talampicillin and was about twice that attained by an equivalent dose of ampicillin. The presence of food in the stomach reduced and delayed the peak blood levels but did not affect the total amount of antibiotic absorbed or the urinary recovery. Talampicillin had less effect on the faecal flora in volunteers than ampicillin, and no overgrowth with Candida spp or Staphylococcus aureus was seen. Thirty-eight out of 47 urinary infections were eradicated by a seven-day course of talampicillin.     

Zwitterionic chitosan derivative, a new biocompatible pharmaceutical excipient, prevents endotoxin-mediated cytokine release

Chitosan is a cationic polymer of natural origin and has been widely explored as a pharmaceutical excipient for a broad range of biomedical applications. While generally considered safe and biocompatible, chitosan has the ability to induce inflammatory reactions, which varies with the physical and chemical properties. We hypothesized that the previously reported zwitterionic chitosan (ZWC) derivative had relatively low pro-inflammatory potential because of the aqueous solubility and reduced amine content. To test this, we compared various chitosans with different aqueous solubilities or primary amine contents with respect to the intraperitoneal (IP) biocompatibility and the propensity to induce pro-inflammatory cytokine production from macrophages. ZWC was relatively well tolerated in ICR mice after IP administration and had no pro-inflammatory effect on naïve macrophages. Comparison with other chitosans indicates that these properties are mainly due to the aqueous solubility at neutral pH and relatively low molecular weight of ZWC. Interestingly, ZWC had a unique ability to suppress cytokine/chemokine production in macrophages challenged with lipopolysaccharide (LPS). This effect is likely due to the strong affinity of ZWC to LPS, which inactivates the pro-inflammatory function of LPS, and appears to be related to the reduced amine content. Our finding warrants further investigation of ZWC as a functional biomaterial.     

Synthesis and anti-Helicobacter pylori activity of FR182024, a new cephem derivative

The synthesis and anti-Helicobacter pylori activity of a novel cephem derivative FR182024 (1) are described. FR182024 having a (5-methyl-1,3,4-thiadiazol-2-yl)-thio moiety at the 3-position and a phenylacetamido at the 7-position was found to have extremely potent in vitro anti-H.pylori activity, superior therapeutic efficacy to AMPC and CAM, and low potential for causing diarrhea.     

Cytotoxic effects of NSL-1406, a new thienopyrimidine derivative, on leukocytes and osteoclasts

We synthesized a series of thienopyrimidine derivatives and examined their cytotoxic effects on several cell lines. One of the derivatives, NSL-1406, was shown to exert potent cytotoxic effects on leukemia cell line including P388 cells and J774 cells. It was also inhibitory on mouse osteoclasts and suppressed the in vitro bone resorption by osteoclasts at nanomolar concentrations.     

Vasoinhibitory effect of NP-252, a new dihydropyridine derivative, in canine cerebral artery

The vasoinhibitory effect of NP-252, a 1,4-dihydropyridine derivative Ca++ antagonist, was examined in canine cerebral artery, and this effect was compared with that of nifedipine. NP-252 (10(-7)M) and nifedipine (10(-6) M) nearly abolished the contraction induced by addition of Ca++ to Ca(++)-free medium containing KC1. NP-252 (10(-6)M) and nifedipine (10(-6)M) attenuated the contraction produced by thromboxane A2 agonist (STA2) in normal medium, and the resultant contractions were 22% (n = 6) and 35% (n = 6) of the control contraction, respectively. The vasoinhibitory effects of NP-252 were significantly stronger than those of nifedipine in canine cerebral artery. NP-252 (10(-7) and 10(-6) M) dose-dependently attenuated nifedipine-resistant Ca(++)-contraction in the presence of STA2 in both canine cerebral and coronary arteries. The inhibitory effect of combined treatment with NP-252 (10(-6) M) and nitroglycerin (10(-6) M) on nifedipine-resistant Ca(++)-contraction in the cerebral artery was additive. These results indicate that NP-252 possesses a stronger vasoinhibitory effect than that of nifedipine in canine cerebral artery.     

Glucoheptonic acid derivative as a new transgalactosylation product

Transgalactosylation is increasingly used for modification of selected compounds because it may introduce new bioactive properties or improve existing ones. This paper presents the application of transgalactosylation activity of Kluyveromyces lactis β-galactosidase (EC 3.2.1.23) for a new derivative of glucoheptonic acid synthesis. The study concerned the impact of following factors on the course of reaction: content and ratio of substrates, enzyme dose, pH of the solution and the presence of salts. In the most favourable conditions (without salt), the final product concentration reached 54.5?g/L, which corresponded to 10.9% of dry matter. Research has shown that higher initial dry matter content results in higher product content (as % dm). The addition of 0.5–0.75?M MgCl₂ or 1?M NaCl led to significantly increased yield. In contrast, the presence of MnCl₂ or the lowest enzyme dose seemed to slow down the synthesis process. Increasing the pH over the optimal value for hydrolytic activity of β-galactosidase caused inhibition of transgalactosylation reaction. The molar ratio of 1.9:1 (sodium glucoheptonate:lactose) was the best among tested options. The described method allowed to successfully obtain a new compound with satisfactory yield in comparison to other transgalactosylation products.