Phosphoinositide 3-kinase (PI3K) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. Wortmannin and its analogues are potent PI3K inhibitors whose therapeutic use has been impeded by inherent defects such as instability and toxicity. Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development.
Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK a values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3 00 -NH 2 reacting with the b-lactam of piperacillin. The order of the pK a values of the nitrogens of tobramycin was determined by 1 H and 15 N NMR titrations to be 6¢-NH 2 42¢-NH 2 41-NH 2 E3 00 -NH 2 43-NH 2 . At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer. The Journal of Antibiotics (2011) 64, 673-677; doi:10.1038/ja.2011.72; published online 3 August 2011Keywords: piperacillin; protonation constants; structure elucidation; tobramycin; Y-site co-administration; Zosyn INTRODUCTION Tobramycin (Figure 1) is an aminoglycoside antibiotic produced by Streptomyces tenebrarius 1 used to treat infections caused by susceptible Gram-negative microorganisms. 2 It is often used in combination with penicillins, such as piperacillin (Figure 2), to treat severe infections caused by Gram-negative bacteria. 3 It is well known that tobramycin reacts with b-lactams, including piperacillin, causing a significant loss of aminoglycoside activity. 4 The inactivation mechanism is thought to involve nucleophilic attack and ring opening of the penicillin b-lactam ring by an amino group of the aminoglycoside. 5,6 The rate of aminoglycoside inactivation is dependent on temperature, time, concentration of the b-lactam and composition of the medium. [7][8][9] Another important factor to consider is the pH of the solution. As the degree of protonation of an amino group increases, it should become less nucleophilic. The amino groups of tobramycin have different pK a values, 10,11 hence, it is logical to assume the reaction would be affected by pH of the solution. Therefore, knowledge of the protonation constants of the amino groups and their order is important in understanding the reactivity of tobramycin with piperacillin at different pHs.Zosyn is an intravenously administered antibiotic, which contains piperacillin and tazobactam (a b-lactamase inhibitor) in an 8:1 ratio. It also contains EDTA and sodium citrate, which is used to buffer the solution at around pH 6. 12 It has been approved for Y-site coadministration with the aminoglycosides amikacin and gentamicin. 13 It has not been approved for co-administration with tobramycin,
SummaryThe extraction of aliphatic and aromatic hydrocarbons from New Albany Shale by supercritical carbon dioxide at different extraction temperatures is described. The main goal of this work was to determine the effect of the temperature on the extraction process (ie. relative extraction rate and efficiency). The data suggest that temperature changes of 20 and 40 degrees for the relatively moderate extraction temperatures tested (55, 75, and 95 "C), can have significant effects on both relative extraction rates and yields. While lower molecular weight aromatics presented exponential extraction profiles, similar to those of the aliphatic hydrocarbons, higher molecular weight aromatics, such as the phenanthrenes, showed a linear extraction profile. This behavior cannot be explained by solubility differences in the supercritical fluid alone, and are, therefore, most likely based on differences in the speciation of the hydrocarbons within the sample matrix. Extractions at elevated temperatures (300 "C) resulted in significant increments in the relative recoveries of all compounds, but particularly for the aromatic hydrocarbons. This may be caused by structural rearrangement of the sample matrix with subsequent release of trapped hydrocarbons and possibly by C-S and S-S bond breakage.
A gram-scale synthesis of [3,[4][5][6][7][8][9][10][11][12][13] C 2 ,1a,7-2 H 2 ]cortisone from prednisone was developed. The deuterium atom at the C-1 position was introduced through a regioselective and stereoselective deuteration of the 1,2-double bond of the 1,4-diene-3-one using Wilkinson's catalyst. After the oxidative cleavage of the A-ring, two carbon-13 atoms were introduced via acetylation of an A-ring enol lactone with [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]acetyl chloride. The steroidal A-ring was then reconstructed to incorporate the carbon-13 atoms into the C-3 and C-4 positions. The deuterium atom at C-7 was introduced through a regioselective deuteration of the 6,7-double bond of a 4,6-diene-3-one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,[4][5][6][7][8][9][10][11][12][13]
Treatment of a variety of tetracyclines (tigecycline, minocycline, tetracycline and doxycycline) with Ag(2)CO(3)/EDTA or Hg(OAc)(2) cleanly gave the 4,11a-bridged derivatives in high yields. The reactions proceeded through a novel, intramolecular Mannich cyclization of an iminium species generated by oxidation of the tertiary dimethylamino group at C(4) by Ag(I) or Hg(II). Tetracyclines without 5-OH-substitution (tigecycline, tetracycline and minocycline) gave the 4-OH-substituted, 4,11a-bridged compound, whereas doxycycline gave the 4-dimethylamino-substituted, 4,11a-bridged product. In the case of tetracycline, the 4,11a-bridged compound can equilibrate further to a 4,6-bridged hemiketal. Some of the bridged compounds underwent a novel decarboxylation--rearrangement sequence under acidic conditions to give tricyclic, open chain 1,4-quinoid compounds.
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