US EPA

7187506 

Journal Article 

Part-1: Design, synthesis and biological evaluation of novel bromo-pyrimidine analogs as tyrosine kinase inhibitors 

Munikrishnappa, CS; Puranik, SB; Kumar, GVS; Prasad, YR; , 

2016 

Yes 

European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 

ISSY-LES-MOULINEAUX 

119 

70-82 

English 

27155464 

10.1016/j.ejmech.2016.04.056 

WOS:000378433600005 

A novel series of 5-bromo-pyrimidine derivatives (5a-1, 6a-h, 9a-m and 10a-d) were synthesized through multi step reactions starting from 5-bromo-2,4-dichloro pyrimidine. The newly synthesized compounds were characterized using elemental analysis and spectral data (IR, H-1 NMR, C-13 NMR and LC-MS) analysis. The titled compounds were evaluated for their in vitro cytotoxic activity against tumor cell lines panel consisted of HGT116 (human colon cancer cell line), A549 (human lung cancer cell line), K562 (human chronic myeloid leukemia cell line), U937 (human acute monocytic myeloid leukemia cell line), and L02 (human normal cell line) by using MTI' assay Mosmann's method. As most of the compounds are highly potent against K562 cells, all the synthesized compounds were evaluated for Bcr/Abl tyrosine kinase inhibitory activity by using well-established ADP-Glo assay method. Dasatinib was utilized as positive control to validate in both biological evaluations.The biological activity revealed that the compounds 5c, 5e, 6g, 9e, 9f and 10c were potent Bcr/Abl kinase inhibitors among the titled compounds. Thus these compounds may be promising lead compounds to be developed as an alternative for current Dasatinib therapy. (C) 2016 Elsevier Masson SAS. All rights reserved. 

5-Bromo-pyrimidine; Anticancer; Cytotoxicity; Dasatinib derivatives; MTT assay; 1 [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl] 3 methyl 1 oxobutan 2 yl carbamate; 4 [4 [3,5 bis(trifluoromethyl)phenylsulfonyl]piperazin 1 yl] 5 bromo 2 chloro pyrimidine; 5 bromo 2 chloro 4 (4 tosylpiperazin 1 yl)pyrimidine; 5 bromo 2 chloro 4 (piperazin 1 yl)pyrimidine dihydrochloride; 5 bromo 2 chloro 4 [4 (3,5 dimethylisoxazol 4 yl sulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (4 fluorophenylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (biphenyl 4 ylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (cyclopropylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (methylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (naphthalen 2 ylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 (propylsulfonyl)piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 [2 nitro 4 (trifluoromethyl) phenylsulfonyl]piperazin 1 yl]pyrimidine; 5 bromo 2 chloro 4 [4 [4 (trifluoromethyl) phenylsulfonyl]piperazin 1 yl]pyrimidine; 5 bromo 2 morpholino 4 [4 [2 nitro 4 (trifluoromethyl) phenylsulfonyl]piperazin 1 yl]pyrimidine; 5 bromo 4 [4 (4 tert butylphenylsulfonyl)piperazin 1 yl] 2 chloro pyrimidine; 5 bromo 4 [4 (substituted sulfonyl)piperazin 1 yl] 2 chloropyrimidine; cytotoxic agent; dasatinib; protein tyrosine kinase inhibitor; pyrimidine derivative; tert butyl 4 (5 bromo 2 chloropyrimidin 4 yl)piperazine 1 carboxylate; unclassified drug; unindexed drug; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl](2 chloro 5 iodophenyl)methanone; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl](2,6 difluorophenyl)methanone; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl](4 fluorophenyl)methanone; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl](4,5,6 trichloropyridin 2 yl)methanone; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl](susbsituted acid)methanone; [4 (5 bromo 2 chloropyrimidin 4 yl)piperazin 1 yl][4 (trifluoromethyl)phenyl]methanone; antineoplastic agent; BCR ABL protein; protein kinase inhibitor; pyrimidine derivative; A549 cell line; antineoplastic activity; Article; controlled study; drug design; drug potency; drug screening; drug synthesis; enzyme inhibition; HCT116 cell line; human; human cell; in vitro study; K562 cell line; structure activity relation; U937 cell line; antagonists and inhibitors; cell proliferation; chemistry; drug effects; synthesis; tumor cell line; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Fusion Proteins, bcr-abl; Humans; Protein Kinase Inhibitors; Pyrimidines