Page 107 - Pharma News Letter - Vol2 Issue 1

Research Publications

New 2-Alkoxycyanopyridine Derivatives As Inhibitors Of
Egfr, Her2, And Dhfr: Synthesis, Anticancer Evaluation, And
Molecular Modeling Studies

Bioorganic And Medicinal Chemistry. 2023 Dec; 141: 106874.
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Samia S Hawas , Selwan M El-Sayed, Perihan A Elzahhar, Mohamed A Moustafa

Abstract

New series of substituted 2-alkoxycyanopyridine derivatives were synthesized and evaluated for
their in vitro and in vivo anticancer activities. Comparing the evaluated activities against cancer
cell lines to the broad-spectrum anticancer doxorubicin, and the kinase inhibitor sorafenib,
compounds 3a, 4b, 4c, 7a, and 8d demonstrated superior anticancer efficacy with elevated safety
profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their
mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed.
The promising synthesized compounds exhibited potent dual kinase EGFR/HER2 inhibitory
activity with IC50 values of 0.248/0.156 μM for 4b and 0.138/0.092 μM for 4c. Additionally,
with IC50 values of 0.138 and 0.193 M, respectively, 4b and 4c had the greatest DHFR inhibitory
activity that was comparable to methotrexate. In the MCF7 breast cancer cell line, they caused
arrest at the S phase of the cell cycle and exhibited apoptosis induction activity. With restored
caspase-3 immunoexpression, the anti-breast cancer assay performed in vivo of 4b and 4c
demonstrated a substantial decrease in tumor volume. Results from molecular modeling were in
agreement with biological assays proving the importance of the 3-caynopyridine, two substituted
phenyl rings attached to central pyridine ring, and propoxy side chain moieties for binding with
the receptors. As 4c works by inhibiting both EGFR/HER2 kinase, DHFR enzymes, in addition
to cellular apoptosis, it could be viewed as a model of compounds possessing a multi-targeting
anticancer activity. Collectively, compounds 4b and 4c might represent prototypes for further
development as anticancer molecules.

Reference:

https://doi.org/10.1016/j.bioorg.2023.106874

Vol. 2 - Issue 1 107