Design, synthesis, and molecular docking of novel indole scaffold‐based VEGFR‐2 inhibitors as targeted anticancer agents

Abstract

A series of new indole derivatives 1-18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

“…For example, sorafenib (I), regorafenib (II), lenvatinib (III), nintedanib (IV), sunitinib (V) and pazopanib (VI) were clinically approved by the FDA for the treatment of different types of cancers ( Figure 1) [10][11][12][13][14]. In addition, different research groups designed and synthesized several promising VEGFR-2 inhibitors for targeted cancer therapy [15][16][17][18][19][20]. Based on the different reported VEGFR-2 crystal structures, VEGFR-2 inhibitors can be classified into three main types.…”

Structure–activity relationship studies of indolin‐2‐one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents

“…However, recently, some indole derivatives have been also reported as VEGFR inhibitors. [23,88] Introduction of diverse substituents at…”

“…However, recently, some indole derivatives have been also reported as VEGFR inhibitors. [ 23,88 ] Introduction of diverse substituents at phenyl ring and C‐3 of oxindole, and also the substituted amine group of the tail, can have an effect on potency, adverse effects, and solubility of indolin‐2‐one derivatives. Several compounds of each series in this review exhibited more potency, high water solubility, and low complications.…”

“…[19] Recently, different small molecules have been designed as VEGFR inhibitors and anticancer agents. [20][21][22][23][24][25][26][27][28] The indolin-2-one analogs have been identified as effective angiogenesis inhibitors and multitargeted tyrosine kinases inhibitors. Sunitinib (SU11248) is the first small molecule possessing the indolin-2-one template against a variety of kinases such as VEGF receptor (VEGFR) types 1 (FLT1), 2 (KDR), and 3 (FLT4); the stem cell factor receptor (c-Kit); platelet-derived growth factor receptors A and B (PDGFRA and PDGFRB); colony-stimulating factor 1 receptor (CSF-1R); FMS-like tyrosine kinase 3 (FLT3); and glial cell line-derived neurotrophic factor receptor (RET), which received FDA approval and was marketed for the treatment of gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC) in January 2006, and for pancreatic neuroendocrine tumors in May 2011.…”

In vitro MAO-B Inhibitory Effect of Citrus trifoliata L. via Enzyme Assay and Molecular Docking Study

“…It also predicts the binding affinity of this compound its target. So, molecular docking is used to explain observed compound experimental activity [19][20][21] or as a tool for further lead optimization [22]. In the current work, the major flavonoid of the hydro alcoholic extract of Citrus trifoliata L. fruit (family Rutaceae) hesperidin was quantitatively quantified by HPLC (Fig.…”