- Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2)
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Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds. Further structure-activity relationship (SAR) studies identified numerous analogues inhibiting TDP2 in low micromolar range without appreciable inhibition against the homologous TDP1 at the highest testing concentration (111 μM). The best compound 64 inhibited recombinant TDP2 with an IC50 of 1.9 μM. The discovery of this chemotype may provide a platform toward understanding TDP2 as a drug target.
- Kankanala, Jayakanth,Marchand, Christophe,Abdelmalak, Monica,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
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supporting information
p. 2734 - 2746
(2016/04/10)
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- TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to substituted five membered heteroaryl benzamide compounds compounds of formula (I), which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 50; 51
(2015/12/08)
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- Divergent cyclisations of 2-(5-amino-4-carbamoyl-1H-pyrazol-3-yl)acetic acids with formyl and acetyl electrophiles
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The reaction of 2-(5-amino-4-carbamoyl-1-methyl-1H-pyrazol-3-yl)acetic acid and triethylorthoformate did not give the expected dihydropyrazolo[4,3-c]pyridin-4-one product as described in literature, but formed an alternative cyclic imide product, fully characterised by NMR and X-ray crystallography. This mode of reaction was shown to be general to other 1-substituted-2-(5-amino-4-carbamoyl-1H-pyrazol-3-yl)acetic acids. The outcome of the cyclisation was highly sensitive both to the nature of the reagents used and also to the acidity of the reaction medium, such that a number of interesting bicyclic heterocycles could be produced in a controlled fashion from the single starting material. The major tautomeric forms of the bicyclic products in solution were found to vary according to their substitution pattern.
- Smyth, Lynette A.,Matthews, Thomas P.,Horton, Peter N.,Hursthouse, Michael. B.,Collins, Ian
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p. 9627 - 9634
(2008/02/11)
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