74481-55-3Relevant articles and documents
Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC
Piizzi, Grazia,Parker, David T.,Peng, Yunshan,Dobler, Markus,Patnaik, Anup,Wattanasin, Som,Liu, Eugene,Lenoir, Francois,Nunez, Jill,Kerrigan, John,McKenney, David,Osborne, Colin,Yu, Donghui,Lanieri, Leanne,Bojkovic, Jade,Dzink-Fox, Joann,Lilly, Maria-Dawn,Sprague, Elizabeth R.,Lu, Yipin,Wang, Hongming,Ranjitkar, Srijan,Xie, Lili,Wang, Bing,Glick, Meir,Hamann, Lawrence G.,Tommasi, Ruben,Yang, Xia,Dean, Charles R.
, p. 5002 - 5014 (2017/06/28)
Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-Acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.
Total synthesis of trunkamide A, a novel thiazoline-based prenylated cyclopeptide metabolite from Lissoclinum sp.
McKeever, Benedict,Pattenden, Gerald
, p. 2713 - 2727 (2007/10/03)
Full details of a total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, are described.
Stereospecific synthesis of functionalized ether phospholipids
Kazi, Abul B.,Shidmand, Sean,Hajdu, Joseph
, p. 9337 - 9347 (2007/10/03)
A new stereospecific synthesis of functionalized alkyl ether phospholipids is reported. The synthesis is based upon the following: (1) the use of (R)-glycidyl tosylate as a chiral glycerol precursor; (2) the opening of a boron trifluoride catalyzed epoxide ring to introduce the functionalized sn-1-alkyl substituents; (3) the role of tetrahydropyranyl in protecting the sn-2-glycerol position; and (4) the elaboration of the sn-3-carbinol function, via the base hydrolysis of the acetoxy intermediate, obtained from the displacement of the toluenesulfonyl group of the substrate in dipolar aprotic media. Phosphorylation, using two different methods, has led to the development of two major classes of alkyllysophospholipids. For preparation of 'modulator-phospholipid' analogues, the substituted glycerol is coupled with 2,2,2-trichloro-tert-butyl phosphodichloridite and an N-protected amino acid ester, while elaboration of the phosphocholine headgroup of the target platelet-activating factor (PAF) analogues is achieved via the 2-chloro-2- oxo-1,3,2-dioxaphospholane/trimethylamine sequence. The synthesis provides rapid and efficient access to both types of phospholipids: (1) construction of the functionalized/substituted glycerol skeleton is achieved in a straightforward four-step sequence in better than 50% overall yield, and (2) phosphitylation or phosphorylation of the respective glycerol intermediates relies on reagents that require minimal use of protecting groups. The phospholipid compounds prepared include (1) the first synthetic analogue exhibiting modulator activity in conjunction with the glucocorticoid-receptor complex and (2) an sn-1-(ωamino)alkyl derivative of PAF, suitable for introduction of chain-terminal spectroscopic labels for biological and physicochemical studies to elucidate the mechanism of action of this highly potent alkyl ether phospholipid. The synthetic methods described herein have a great deal of flexibility, thus providing convenient general routes to a wide range of alkyl ether phospholipids.
