Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 16, Pages 3521-3526Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.05.061
Keywords
Similarity searching; Phospholipase C; Molecular modelling; NCI60; MTT; Structure activity relationship (SAR)
Funding
- Faculty Research Developmental Fund, Faculty of Science, University of Auckland [3700449]
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Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI(50) at 30 nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI(50) = 296 nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various sub-stituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found. (C) 2016 Elsevier Ltd. All rights reserved.
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