Design, synthesis and docking study of pyridine and thieno[2,3-b] pyridine derivatives as anticancer PIM-1 kinase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2018.07.024

A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 μM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI₅₀ values 0.302–3.57 μM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC₅₀ = 0.019 μM followed by 5b, 15e, 10c and 13h with IC₅₀ values 0.044, 0.083, 0.128 and 0.479 μM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.

Full text of DOI:10.1016/j.bioorg.2018.07.024

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Accepted Manuscript
Design, Synthesis and Docking Study of Pyridine and Thieno[2,3-b] pyridine
Derivatives as Anticancer PIM-1 Kinase inhibitors
Marwa E. Abdelaziz, Mostafa M.M. El-Miligy, Salwa M. Fahmy, Mona A.
Mahran, Aly A. Hazzaa
PII:
S0045-2068(18)30408-5
DOI:
https://doi.org/10.1016/j.bioorg.2018.07.024
YBIOO 2443
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 April 2018
19 July 2018
20 July 2018
Please cite this article as: M.E. Abdelaziz, M.M.M. El-Miligy, S.M. Fahmy, M.A. Mahran, A.A. Hazzaa, Design,
Synthesis and Docking Study of Pyridine and Thieno[2,3-b] pyridine Derivatives as Anticancer PIM-1 Kinase
inhibitors, Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/j.bioorg.2018.07.024
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Design, Synthesis and Docking Study of Pyridine and Thieno[2,3-b]
pyridine Derivatives as Anticancer PIM-1 Kinase inhibitors
Marwa E. Abdelaziz*, Mostafa M. M. El-Miligy, Salwa M. Fahmy, Mona A. Mahran, Aly A.
Hazzaa
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University,
Alexandria 21521, Egypt
*Author for correspondence:
Tel: +20 1285838955
Fax: ‏+20 34873273
marwaehab22@yahoo.com
Abstract
A series of pyridine and thieno[2,3-b]pyridine derivatives have been
designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven
compounds were selected by NCI to be tested initially at a single dose (10 µM)
in the full NCI 60 cell line panel. Compound 5b showed potent anticancer
activity and was tested twice in the five-dose assay which confirmed its potent
antitumor activity (GI50 values 0.302 to 3.57 µM) against all tested tumor cell
lines except six cell lines where they showed moderate sensitivity. This
compound was sent to NCI biological evaluation committee and still under
consideration for further testing. In addition, the most active anticancer
compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their
PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with
IC50 = 0.019 µM followed by 5b, 15e, 10c and 13h with IC50 values 0.044,
0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most
active compounds inPIM-1 kinase active site was consistent with the in vitro
activity.
Keywords:
Pyridine
Thieno[2,3-b]pyridine
PIM-1 Kinase inhibitors
Anticancer
1. Introduction
1

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PIM kinases are serine/threonine kinases and include PIM-1, PIM-2, and
PIM-3 subtypes. PIM kinases have a special hinge region sequence [1-3]. PIM-1
kinase is an important drug target against different malignancies as it
participates in the progression and initiation of lymphomas, leukemia and solid
tumors such as prostate, pancreas and colon [4]. Also, it is associated with
several cellular functions such as survival, apoptosis, differentiation and
proliferation. Dysregulation of PIM-1 kinase promotes carcinogenesis of
different types of tumors. Thus, PIM-1 kinase inhibition is an important strategy
for treatment of different types of tumor. It was reported that, 4,6-diaryl-3-
cyano-2-pyridone derivatives showed potent anticancer activity through
inhibition of PIM-1 kinase. For example, compound I was declared as a potent
PIM-1 kinase inhibitor with IC50 = 0.050 µM [5]. In addition, compound II
showed potent anticancer and PIM-1 kinase inhibitory activity with IC50 = 0.94
µM [6]. On the other hand, bio isosteric replacement of 2-hydroxy group to 2-
amino as in compounds III and IV retained potent PIM-1 inhibitory activities
with IC50 =0.058 µM and 0.0111 µM respectively [7]. Furthermore, the fusion
of pyridine with five or six membered heterocyclic moieties like pyrazole in
compound V or pyridine in compound VI revealed potent PIM-1 inhibitors with
IC50 = 0.00003 μM and 0.001 μM respectively [8] (figure 1). This indicates the
potentiality of 4,6-diaryl-3-cyano-2-substitutedpyridine skeleton as a template
for further optimization to get more potent PIM-1 kinase inhibitor.
2

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Figure 1: Reported pyridine derivatives as PIM-1 kinase inhibitors
In the present investigation, new pyridine derivatives were designed to
keep the structural features for PIM-1 kinase inhibition. Pyridine ring was
substituted at position 4 by aromatic moiety which was substituted with either
hydrophilic or lipophilic groups. Also, pyridine ring was substituted at position
6
with 2,5-dihydroxyphenyl,
2-hydroxy-5-methoxyphenyl or 2,5-
dimethoxyphenyl. Moreover, the oxygen at position 2 of pyridine was
bioisosterically replaced by either sulfur or nitrogen. In addition, the pyridine
ring was fused with five membered heterocyclic thiophene moiety to increase
the rigidity of the molecule in order to study the effect of these structural
variations on the interaction with the PIM-1 kinase hence the anticancer activity
(figure 2).
3