Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors

Abstract

The vascular endothelial growth factor (VEGF) signaling pathway plays pivotal role in regulating tumor angiogenesis. VEGF as a therapeutic target has been validated in various types of human cancers [1]. The VEGF receptor 2 (VEGFR-2) represents a major target within the angiogenesis-related kinases, hence considered the most important transducer of VEGF-dependent angiogenesis [2]. Thus, inhibition of VEGF/ VEGFR signaling pathway is regarded as an attractive therapeutic target for inhibition of tumor angiogenesis and subsequent tumor growth [3–5]. Phthalazin-1,4-diones have been reported as potent type II IMP dehydrogenase inhibitors and as effective anti-proliferative agents against different human and murine tumor cells particularly against hepatocellular carcinoma [4]. Moreover, 1,4-disubstituted phthalazines have attracted considerable attention as promising and effective anticancer agents [4, 5]. For example, 1-piperazinyl-4-substitutedphthalazines have been reported as active cytotoxic agents against A549, HT-29, and MDAMB231 [4]. Two studies reported the cytotoxicity of a series of 1-anilino-4-(arylsulfinyl/sulfonylmethyl)phthalazines against Bel-7402 (human liver cancer cell line) and HT-1080 (human fibrosarcoma cell line)