Synthesis, biological evaluation and molecular docking studies of Combretastatin A-4 phosphoramidates as novel anticance
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02632-2
ORIGINAL RESEARCH
Synthesis, biological evaluation and molecular docking studies of Combretastatin A-4 phosphoramidates as novel anticancer prodrugs Shaowu Zhang1 Tang Li1 Wan Pang1 Jingjing Wu1 Fulong Wu1 Yangyang Liu1 Fanhong Wu1 ●
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Received: 13 May 2020 / Accepted: 3 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract A new series of CA4P analogs (5a-g, 6a-g) has been designed and effectively synthesized via a one-pot reaction from Combretastatin A-4/Erianin, commercially available amino acid esters and phenyl dichlorophosphate. To establish new candidates with anticancer activity, the in vitro antiproliferative effect of these compounds was measured by the CCK8 method on different cancer cell lines such as human liver caricinoma (HepG2), cervical cancer (HeLa) and colorectal carcinoma (HCT-116). The structure-activity relationships between CA4P outgrowth-promoting activity and its analogs suggested that the biaryl structure linked with double bond in Part A and the steric effect at the position α-carbon atom in the amino acid ester moiety (Part B) are essential for affecting the in vitro proliferation inhibitory activity of CA4P analogs. Additionally, the results of biological activity and molecular docking simulation showed that the vast majority of these novel Phosphoramidate derivatives exhibited potent anti-cancer activities. Graphical Abstract
Keywords Combretastatin A-4 Phosphoramidate Anti-proliferative activity Molecular docking ●
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Introduction Cancer, a disease that involves the uncontrolled growth of abnormal cells anywhere in a body, has remained one of the leading causes of human death globally [1]. In the last three
* Wan Pang [email protected] * Fanhong Wu [email protected] 1
College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
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decades, chemotherapy has been the main modality of treatment for cancer patients. However, its effectiveness remains low, primarily due to limited accessibility of drugs to the tumor tissue, their intolerable toxicity, development of muti-drug resistance, and the dynamic heterogeneous biology of the growing tumors [2]. Therefore, the discovery of new compounds with selective activity against cancerous cells is the center of attention of anticancer drug development. CA4P is a synthetic water-soluble phosphorylated prodrug of combretastatin A4 (CA-4, Fig. 1), isolated from the South African willow bush, combretum caffrum. What is more, CA4P as a tumor vascular targeting agent is currently in clinical trial [3–5]. In animal models, CA4P reversibly binds to the colchicine binding site of endothelial cell
Medicinal Chemistry Research
tubulin, inhibiting tubulin polymerization and selectively inducing mitotic arrest and apoptosis in cancer cells but not in normal cells [6]. As apoptotic endothelial cells detach from their substrate, the detachment can
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