Design, synthesis and biological evaluation of novel 1,5-disubstituted isatin derivatives as antitumor agents
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02627-z
ORIGINAL RESEARCH
Design, synthesis and biological evaluation of novel 1,5-disubstituted isatin derivatives as antitumor agents Huijun Zhuo1 Zhen Zhang1 Yang Liu2 Jingya Zhang1 Guisen Zhao1 ●
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Received: 10 July 2020 / Accepted: 29 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Isatin (1H-indole-2,3-dione) was reported to possess anticancer activities through its effect on tumor proliferation, apoptosis, and metastasis in vitro and in vivo. Here, we described the synthesis of a novel series of 1,5-disubstituted isatin derivatives with 2-indolinone scaffold as antitumor agents. Most of the synthesized compounds revealed potent antiproliferative effects in mantle cell lymphoma (MCL) cell lines, among which 7l possessed promising activities with IC50 values ranging from 0.4 to 1.3 μM. Following flow cytometric analysis, compound 7l efficiently arrested the cell cycle at G2/M phase, and induced apoptosis. Thus, this study shows promise in therapeutics of 1,5-disubstituted isatin derivatives in MCL and provides novel potential and efficient antitumor agents. Graphical Abstract
Keywords Apoptosis Isatin derivatives Mantle cell lymphoma Antitumor ●
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Introduction Apoptosis, an evolutionary highly conserved form of programmed cell death, refers to the orderly death of cells controlled by genes in order to maintain a stable internal environment [1, 2]. Apoptosis can be triggered by extrinsic and intrinsic death receptors, and the intrinsic pathway is closely regulated by the B-cell lymphoma 2 (Bcl-2) family of intracellular proteins [3–6]. Escaping apoptotic cell death
* Guisen Zhao [email protected] 1
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 Shandong, PR China
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Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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machinery is a hallmark of cancer [7, 8]. Mutagenic inactivation of apoptotic proteins and overexpression of antiapoptotic proteins have been found in a variety of cancers, which are the cause of cell proliferation [5, 7, 9]. Mantle cell lymphoma (MCL) is a highly aggressive form of non-Hodgkin-lymphoma (NHL) with a median survival of ~3–5 years and accounts for 6–8% of NHL [10–12]. In spite of the low incidence rate, MCL is considered to be incurable in clinic due to poor prognosis and limited survival [13]. Increased expression of antiapoptotic proteins BCL-2, MCL-1, and Bcl-xL, and loss of proapoptotic proteins BIM is common in MCL [14–16]. Accumulating evidence suggests that the pathogenetic processes of MCL is related to impaired apoptosis regulation [14, 17–19]. Targeting antiapoptotic molecules to induce apoptosis is emerging as a promising therapeutic strategy in MCL. Isatin (1H-indole-2,3-dione, Fig. 1) and its derivatives can pa
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