- Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors
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The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 1/4M. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.
- Qin, Wen-Wen,Sang, Chun-Yan,Zhang, Lin-Lin,Wei, Wei,Tian, Heng-Zhi,Liu, Huan-Xiang,Chen, Shi-Wu,Hui, Ling
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p. 174 - 184
(2015/03/31)
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- COMPOSITION AND METHOD FOR THE TREATMENT OF DISEASES AFFECTED BY A PEPTIDE RECEPTOR
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The present invention includes peptidomimetic compound compositions and methods of making peptidomimetic compounds. The peptidomimetic includes an oligo-ben/amide compound having at least three optionally substituted benzamidcs. The present invention also
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Page/Page column 44-45
(2008/12/07)
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- Facile synthesis of benzamides to mimic an α-helix
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A new α-helix mimetic was designed by using a benzamide as a rigid scaffold. It presents three functional groups corresponding to side chains of amino acids found at the i, i + 4, and i + 7 positions of an ideal α-helix, which are displayed on the same he
- Ahn, Jung-Mo,Han, Sun-Young
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p. 3543 - 3547
(2008/02/06)
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- Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors
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Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. Copyright (C) 1999 Elsevier Science Ltd.
- Qian, Yimin,Marugan, Juan Jose,Fossum, Renae D.,Vogt, Andreas,Sebti, Said M.,Hamilton, Andrew D.
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p. 3011 - 3024
(2007/10/03)
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- Inhibitors of prenyl transferases
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Compounds which inhibit prenyl transferases, particularly farnysyltransferase and geranylgeranyl transferase I, processes for preparing the compounds, pharmaceutical compositions containing the compounds, and methods of use.
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- Inhibitors of farnesyltransferase
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Peptidomimetics of the formula CβX where C is cysteine, X is any naturally occuring amino acid, and β is a hydrophobic spacer, most notably 2-phenyl-4-aminobenzoic acid. These compounds are effective inhibitors of p2lras farnesyltrasferase, block Ras-dependent oncogenic signalling and inhibit human tumor growth in vivo in animal models. Pro-drugs made by functionalizing terminal amino and carboxylic acid groups of peptides and peptidomimetics are also disclosed. Such functionalized derivatives demonstrate increased cell uptake. Other structural modifications are also disclosed.
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