- Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors
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Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
- Bo, Yong-Xin,Chen, Shi-Wu,Hao, Shu-Yi,Wang, Xing-Rong,Xiang, Rong,Xu, Yu
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- An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777
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This report describes a new convergent, selective, and economical synthesis of DMP 777, ending with the coupling of the chiral β-lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the β-lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-α-methylbenzylamine and the corresponding butyrophenone.
- Storace, Louis,Anzalone, Luigi,Confalone, Pat N.,Davis, Wayne P.,Fortunak, Joseph M.,Giangiordano, Mark,Haley Jr., James J.,Kamholz, Kenneth,Li, Hui-Yin,Ma, Philip,Nugent, William A.,Parsons Jr., Rodney L.,Sheeran, Patrick J.,Silverman, Charlotte E.,Waltermire, Robert E.,Wood, Christopher C.
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- Synthesis of 4-(4-guanidinobenzoyloxy)benzamides and 1-(4-guanidinobenzoyloxy)benzoyloxy acetamides as trypsin inhibitors
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Seventeen new compounds of 4-(4-guanidinobenzoyloxy)benzamides and 4-(4-guanidinobenzoyloxy)benzoyloxyacetamides were prepared and their inhibitory activities on trypsin, thrombin and porcine pancreatic elastase were measured. These compounds were found to be selective trypsin inhibitors with inhibiting activities from 0.44 to 43 μM.
- Zlatoidsky,Maliar
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p. 895 - 899
(2007/10/03)
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- Degradation kinetics of DMP 777, an elastase inhibitor
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Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development. Methods. The pK(a) was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples. Results. The pK(a) for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is B(AC)2 which involves β-lactam ring opening. The elactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k(OH) controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the β-lactam nitrogen making it a good leaving group. Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.
- Raghavan, Krishnaswamy S.,Gray, David B.,Scholz, Thomas H.,Nemeth, Gregory A.,Hussain, Munir A.
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p. 1815 - 1820
(2007/10/03)
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