الفهرس 
CancerOnly 14 pages are availabe for public view
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Abstract
Cancer is an enormous global health burden. It may affect humans of all ages,
regions and socioeconomic levels. According to statistics from the American Cancer Society,
cancer is the second most lethal disease after cardiovascular diseases, infectious and
parasitic diseases. Hence, the medical needs for cancer remain one of the most demanding
areas in scientific research. A major problem in treating cancer is the fact that it is not a
single disease. There are more than 200 different cancers resulting from different cellular
defects.
The growth of new blood vessels (angiogenesis) is one of the well-established
hallmarks in the process of carcinogenesis. Vascular endothelial growth factor receptor-2
(VEGFR-2) plays a crucial role in cancer angiogenesis. By targeting VEGFR-2, angiogenesis
is greatly inhibited leading to the death of the tumor cells. Induction of angiogenesis is
thought to be required for the ongoing growth of human tumors and consequently,
targeting angiogenesis via inhibition of the VEGF pathway has been a prevalent approach
to cancer therapy.
In this study, a series of novel, pyrano /pyrido thieno[2,3-d]pyrimidine basedderivatives
were designed and synthesized as VEGFR-2 inhibitors, in accordance to the
structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The
synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase
enzyme as targeted angiogenesis inhibitors. The design focused on exploration of the
previous revealed SAR studies, bioisosteric modifications of the lead compounds both in
market and in clinical studies, and identification of the key interactions with the binding
site in silico.
Some compounds (Xd, XVId,XVIg) demonstrated high VEGFR-2 inhibition with IC50 values
(2.5μM,5.48 μM,2.27 μM) respectively. Although the rest of the synthesized thieno[2,3-
d]pyrimidine based-derivatives exhibited moderate to good VEGFR-2 inhibition from( 50-
78%). The anti-proliferative activity against specific types of cancer including Renal cancer,
A498 cell line displayed 77.8% inhibition ,while on breast cancer cell line T-47D exhibited
85.5% inhibition and more than 64-65% inhibition on ovarian cancer, on both IGROV-1 and
SK-OV-3 cell lines .