Background:
Extensive studies were reported in the synthesis of several phthalazine derivatives as
promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine
published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to
the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective
of present research work is the synthesis of new agents with the same essential pharmacophoric features
of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our
molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different
positions.
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Material and Methods: A correlation between structure and biological activity of our designed phthalazines was
established using molecular docking and VEGFR-2 kinase assay.
Results and Discussion:
In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives
5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and
evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma
and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both
HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities
against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively
while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer
with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent
VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine
compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b
emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03
and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular
docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict
their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested
compounds. Most of our designed compounds exhibited good ADMET profile.
Conclusion:
The obtained results showed that, the most active compounds could be useful as a template for
future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors
with higher anticancer analogs.
The expression of LRRN4 was correlated with the progression and prognosis of colon adenocarcinoma (COAD) patients
