Bioorganic & Medicinal Chemistry Letters
Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazo-
line and diarylamide fragments
Ru Wanga, Hu Liua, Yuan-Yuan Youa, Xin-Yu Wanga, Bing-Bing Lva, Li-Qin Caoa, Jia-Yu Xueb,
,
,*
Yun-Gen Xua *, Lei Shia
a Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
b Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
VEGF/VEGFR-2 signaling plays a critical part in tumor angiogenesis. Inhibition of this pathway has been
considered as a promising approach for cancer treatment. In this work, a series of 6,7-dimethoxy-4-anilinoqui-
nazoline derivatives bearing diarylamide moiety were designed, synthesized and evaluated as potent in-
hibitors of VEGFR-2 kinase. Their in vitro antiproliferation activities against two human cancer cell lines Hep-G2
and MCF-7 have also been determined. Among them, compound 14b exhibited the most potent inhibitory ac-
tivity against VEGFR-2 with IC50 value of 0.016 ± 0.002 µM and it showed the most potent antiproliferative
effect against Hep-G2 and MCF-7 with IC50 values at low-micromolar range. Molecular docking studies revealed
that these compounds represented by the most potent compound 14b could bind well to the ATP-binding site of
VEGFR-2, which suggested that compound 14b could be a potential anticancer agent targeting VEGFR-2.
VEGFR-2
Inhibitor
6,7-Dimethoxy-4-anilinoquinazoline
Diarylamide
Cancer
Protein kinases constitute one of the largest protein families. By
multisite phosphorylation, they direct the activity, localization and
function of many proteins, and serve to regulate a wide variety of
cellular processes.1 However, deregulation of protein kinases, which
trigger alteration in kinase-mediated signal transduction, is closely
related to many diseases, such as cancer, diabetes, and immunological,
inflammatory, degenerative and cardiovascular disorders.2 The estab-
lished druggability and the clinical safety profile of approved protein
kinase inhibitors make protein kinases attractive as drug targets.3
Angiogenesis, the growth of new blood vessels from existing vascu-
lature, is essential for normal organ growth and wound repair.4,5
However, an imbalance in this process is involved in a multitude of
pathological events, including cancer, psoriasis, rheumatoid arthritis,
endometriosis, multiple sclerosis, diabetic retinopathy, obesity, and
asthma.4–6 In terms of cancer, solid tumors cannot grow beyond a crit-
ical size without developing new blood vessels to provide oxygen and
nutrients and to dispose of metabolic wastes.7 Hence, blocking angio-
genesis could be a strategy to arrest tumor growth. A number of
proangiogenic regulators, such as vascular endothelial growth factor
(VEGF), epidermal growth factor (EGF), platelet-derived growth factor
(PDGF), transforming growth factor–β (TGF-β), fibroblast growth factor
(FGF), angiopoietins, integrins, and matrix metalloproteinases (MMPs),
have been identified.8,9 Among them, VEGF has been identified as the
most important regulator of tumor angiogenesis, mainly mediated
through a specific receptor tyrosine protein kinase — vascular endo-
thelial growth factor 2 (VEGFR-2, also known as KDR or FLK1).10
Binding of VEGF to VEGFR-2 leads to receptor dimerization, followed by
autophosphorylation of specific tyrosine residues in the intracellular
kinase domain, which initiates a typical receptor signal transduction
cascade and activates a network of distinct downstream signaling
pathways, ultimately leading to angiogenesis, vascular permeability
enhancement, tumor proliferation, and tumor migration.11,12 The
expression of VEGF is commonly upregulated in tumor microenviron-
ment characterized by insufficient oxygenation (hypoxia), acidic pH
(acidosis), and elevated levels of reactive oxygen species (ROS), which is
correlated with tumor progression and poor prognosis in patients with
solid tumors.13 Besides, VEGFR-2 is overexpressed in some malignancies
such as breast cancer, ovarian cancer, thyroid cancer, and hepatocellular
carcinoma.14–17 Therefore, inhibition of VEGF/VEGFR-2 signaling has
been considered one of the most attractive approaches for the treatment
of cancer. Indeed, several VEGFR-2 kinase inhibitors, namely sorafenib
(1), sunitinib (2), pazopanib (3), vandetanib (4), axitinb (5), lenvatinib
(6), regorafenib (7) and cabozantinib (8) (Fig. 1), have been approved
by the Food and Drug Administration (FDA) for the treatment of various
* Corresponding authors.
Received 9 September 2020; Received in revised form 1 January 2021; Accepted 10 January 2021
Available online 16 January 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.