الفهرس | Only 14 pages are availabe for public view |
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 . |