Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents
Ying-Qian LiuXiao-Jing LiChun-Yan ZhaoXiang NanJing TianSusan L. Morris‐NatschkeZhi‐Jun ZhangXiao-Ming YangYang LiuLinhai LiXing-Wen ZhouKuo‐Hsiung Lee
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HeLa
Combretastatin
The synthesis of different 4-arylcoumarin analogues of combretastatin A-4 led to the identification of two new compounds (1 and 2) with potent cytotoxic activity on a CEM leukemia cell line and a third one completely inactive (compound 3). It was suggested that the cytotoxicity of compounds 1 and 2 may be related to their interaction with microtubules and tubulin, since these compounds inhibit microtubule formation from purified tubulin in vitro [Bailly et al. (2003) J. Med. Chem. 46 (25), 5437−5444]. In the present study, tubulin was identified as the main target of these molecules. We studied structure−activity relationships of these compounds using biological experiments specific for tubulin binding. The modification of cell cycle progression induced by compounds 1 and 2 was characterized by an apoptotic induction on human breast cells (HBL100). In addition, these two molecules disturbed cell survival by depolymerizing the microtubule network, leading to a mitotic block. We then determined the thermodynamic parameters of their interaction with purified tubulin by fluorescence spectroscopy and isothermal microcalorimetry. These results, together with a superimposition of the molecule on colchicine in the X-ray-determined three-dimensional structure model of tubulin−colchicine complex, allowed us to identify the pharmacophore of the combretastatin A-4 analogues responsible for their biological activity.
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Colchicine
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Combretastatin
Chalcone
Colchicine
Antimitotic Agent
K562 cells
Chronic myelogenous leukemia
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Combretastatin
Wittig reaction
Suzuki reaction
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AIM: To investigate the possible roles of the cell cycle regulators atm,chk2 and p53 in DDP induced-apoptosis in HeLa cells.METHODS: The proliferation inhibitory rates of HeLa cells induced by different concentrations of DDP were observed by MTT assays.The mRNA and protein expressions of atm,chk2 and p53 in HeLa cells treated with or without DDP were detected by RT-PCR and Western blot,respectively.Cell cycle analysis was performed by flow cytometry.RESULTS: DDP inhibited the proliferation of HeLa cells in a dose and time dependent manner.The mRNA and protein expressions of atm,chk2 and p53 increased in DDP-treated HeLa cells.The apoptosis increased and the cell cycle was arrested in G2/M phase in DDP-treated HeLa cells(P0.05).CONCLUSION: The activation of atm,chk2 and p53 may be related to apoptosis and cell cycle arrest.Targeting ATM,chk2 and p53 pathway may be a promising strategy to increase the sensibility to DDP in cervical cancer.
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Checkpoint Kinase 2
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Tetrahydroisoquinoline (THIQ) 6-O-sulfamate-based anticancer agents, inspired by the endogenous steroid 2-methoxyestradiol and its sulfamate derivatives, are further explored for antiproliferative and microtubule disruptor activity. Based on recently designed C3-methyl C7-methoxy-substituted THIQ derivatives, compounds with mono- and dichloro-substitutions on the pendant N-benzyl ring were synthesized and evaluated. Although improved antiproliferative activity was observed, for example, 4a versus 4b and 4b versus 8c, it was relatively modest. Compound 8c, a 2',5'-dichlorobenzyl derivative was, however, identified as a promising antiproliferative agent with in vitro activities exceeding that of the parent steroid (e.g., GI50 90 nM in DU-145 cells) and was highly potent against a range of tumor cell lines (e.g., GI50 26 nM for OVCAR-3). 8c inhibited the polymerization of tubulin in vitro with an IC50 only twofold less potent than combretastatin A-4 and inhibited colchicine binding to tubulin. Tubulin polymerization assays showed the parent THIQ 4a to be only a very weak inhibitor, but a striking potency difference was seen between compounds with C2' methoxy and chloro substituents, whereas this was much smaller when these substituents were positioned at C5'. To confirm the target in atomic detail and because 8c is a racemic mixture, an achiral parent THIQ 6-O-sulfamate derivative 10 was successfully cocrystallized with the αβ-tubulin heterodimer. The derivative 10 binds at the colchicine site on tubulin, the first example of this compound class investigated in such detail, with its sulfamate group interacting with residues beyond the reach of colchicine itself, similar to a recently reported quinazolinone sulfamate derivative, 6a. The structure also suggests that for racemic C3-methyl-substituted THIQ derivatives, such as 8c, the (S)-enantiomer is likely to be preferentially accommodated within the colchicine site for steric reasons. The results further confirm the potential of nonsteroidal THIQ sulfamate derivatives for oncology and suggest that the mechanism of microtubule destabilization for the THIQ compound class is to prevent the curved-to-straight conformational transition of tubulin required for polymerization.
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Recent studies have shown an overexpression of γ-tubulin in human glioblastomas and glioblastoma cell lines. As the 2-year survival rate for glioblastoma is very poor, potential benefit exists for discovering novel chemotherapeutic agents that can inhibit γ-tubulin, which is known to form a ring complex that acts as a microtubule nucleation center. We present experimental evidence that colchicine and combretastatin A-4 bind to γ-tubulin, which are to our knowledge the first drug-like compounds known to interact with γ-tubulin. Molecular dynamics simulations and docking studies were used to analyze the hypothesized γ-tubulin binding domain of these compounds. The suitability of the potential binding modes was evaluated and suggests the subsequent rational design of novel targeted inhibitors of γ-tubulin.
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We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A‐4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed. The dynamics of microtubule polymerization was investigated by means of immunofluorescence assays. It was thus established that at least some of the compounds under study exert their cytotoxic action by means of interaction with tubulin.
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Combretastatin
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Tubulin plays an important role in cell growth,morphological maintenance,signal transduction and mitotic process.Tubulin inhibitors are the popular antitumor drugs in recent years.Combretastatin A-4(CA-4) is one of the tubulin inhibitors,which is extracted and isolated from the Combretum caffrum in South African.It is one of the most active compounds with tubulin-inhibiting activity,but has many defects.Currently,researchers have designed other derivatives,focusing on how to improve the water solubility while keep the yield-configuration.In this article we reviewed the structure modification and the progress in CA-4 analogue design.
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Antimitotic Agent
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