Identification of anticancer agents based on the thieno[2,3-b]pyridine and 1H-pyrazole molecular scaffolds.
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 GI50 at 30nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50=296nM (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 substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found.
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Chatchakorn
C
Eurtivong
Cell Biology Unit, Department of Pathology, Landspítali University Hospital, Reykjavík, Iceland.
Inga
I
Reynisdóttir
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Stephanie
S
Kuczma
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Daniel P
DP
Furkert
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Margaret A
MA
Brimble
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: j.reynisson@auckland.ac.nz.
Jóhannes
J
Reynisson
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011725:Pyridines; C000618478:thieno(2,3-b)pyridine
MTT; Molecular modelling; NCI60; Phospholipase C; Similarity searching; Structure activity relationship (SAR)