10159-53-2Relevant articles and documents
The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions
Shulman-Roskes, Ellen M.,Noe, Dennis A.,Gamcsik, Michael P.,Marlow, Allison L.,Hilton, John,Hausheer, Frederick H.,Colvin, O. Michael,Ludeman, Susan M.
, p. 515 - 529 (1998)
NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 °C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55- 76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.
Improving nature's enzyme active site with genetically encoded unnatural amino acids
Jackson, Jennifer C.,Duffy, Sean P.,Hess, Kenneth R.,Mehl, Ryan A.
, p. 11124 - 11127 (2006)
The ability to site-specifically incorporate a diverse set of unnatural amino acids (>30) into proteins and quickly add new structures of interest has recently changed our approach to protein use and study. One important question yet unaddressed with unnatural amino acids (UAAs) is whether they can improve the activity of an enzyme beyond that available from the natural 20 amino acids. Herein, we report the >30-fold improvement of prodrug activator nitroreductase activity with an UAA over that of the native active site and a >2.3-fold improvement over the best possible natural amino acid. Because immense structural and electrostatic diversity at a single location can be sampled very quickly, UAAs can be implemented to improve enzyme active sites and tune a site to multiple substrates.
Aldophosphamide Acetal Diacetate and Structural Analogues: Synthesis and Cytotoxicity Studies
Wang, Yuqiang,Farquhar, David
, p. 197 - 203 (2007/10/02)
The synthesis of aldophosphamide acetal diacetate and a number of structural analogues is described.These compounds are designed to undergo biotransformation to the corresponding aldehydes in the presence of carboxylate esterases, enzymes that are ubiquitous in mammalian tissue.Several of these aldehydes can theoretically exist in pseudoequilibrium with the 4-hydroxyoxazaphosphorine tautomers; others lack this capability.The half-lives of the acetals in 0.05 M phosphate buffer, pH 7.4, at 37 deg C ranged from 1 to 2 days.In the presence of 2 unit equiv of porcine liver carboxylate esterase, all of the compounds were hydrolyzed with half-lives of less than 1 min.Although closely structurally related, the compounds exhibited a wide range of cytotoxicities to L1210 murine leukemia cells in vitro.
