Synthesis and Biological Evaluation of 1-Benzylidene-3, 4-Dihydronaphthalen-2-one as a New Class of Microtubule-Targeting Agents

ArticleinJournal of Medicinal Chemistry 55(12):5720-33 · June 2012with19 Reads
Impact Factor: 5.45 · DOI: 10.1021/jm300596s · Source: PubMed

A series of 1-benzylidene-3,4-dihydronaphthalen-2-one derivatives were designed and synthesized, and their biological activities in vitro and in vivo were evaluated. The results showed a number of the title compounds exhibiting potent nanomolar activity in several human cancer cell lines. Of these, compound 22b showed the strongest inhibitory activity against human CEM, MDA-MBA-435, and K562 cells (IC(50) = 1 nM), displayed in vitro inhibition of tubulin polymerization (IC(50) = 3.93 μM), and significantly induced cell cycle arrest in G2/M phase. In addition, compound 22b could inhibit the tumor growth in colon nude mouse xenograft tumor model significantly and seemed safer than CA-4 when achieving a similar tumor suppression. This study provided a new molecular scaffold for the further development of antitumor agents that target tubulin.

    • "The vast majority of CA-4 analogues were obtained by linker modifications with different heterocycles (or other fragments), along with variations of the substituents on the phenyl rings (see Beale et al., 2012; O'Boyle et al., 2013; Gill et al., 2014; Hsein et al., 2005; Ji et al., 2015; Lee et al., 2011; Liu et al., 2012; Maya et al., 2005; Nam et al., 2003; Romagnoli et al., 2012 Romagnoli et al., , 2013 Singh et al., 2009; Tsyganov et al., 2013 and Zheng et al., 2014 for recent examples). The activity of the resulting compounds was found to be highly sensitive to the distance between the rings and their relative spatial orientation. "
    [Show abstract] [Hide abstract] ABSTRACT: Compounds interacting with cell protein tubulin and microtubules represent an important type of antimitotic agents. A series of tubulin-targeted 2-aryl-4-benzoyl-imidazoles were reported to possess high cytotoxicity, and so, we prepared a series of structural isomers of these to be evaluated as antimitotic agents. The synthesis of the novel (Z)-2-aryl-5-arylmethylidene-3,5-dihydro-4H-imidazol-4-ones involved coupling of substituted hippuric acids with aromatic aldehydes. Subsequent conversion of the resulting oxazolones to the corresponding imidazolones was carried out under microwave irradiation in the presence of urea and ammonium acetate. The cytotoxicity of the majority of the compounds to human epithelial carcinoma cancer cell line A549 was in the sub-micromolar range and was found to be more sensitive to the substituents on the 5-arylmethylidene fragment than on the 2-aryl ring in general. The cytotoxicities of the synthesized compounds were lower than those of the previously reported isomeric 2-aryl-4-benzoyl-imidazoles, and the basic structure–activity relationships in the isomeric pairs were different. Synthesized (5Z)-5-[(4-bromophenyl)methylidene]-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one, which had the highest cytotoxicity (IC50 ~ 440 nM) in the series of novel compounds, had a definite cytostatic effect on the A549 cells, but its antiproliferative properties were not linked to action on the microtubules. This would be an interesting lead compound for additional investigation into the mechanism of cytostatic action, and further structural optimization.
    No preview · Article · Apr 2016 · Medicinal Chemistry Research
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    • "To further improve the anti-tumor property, MET-Har-02 bearing N 2 -benzylated modification in position 2 was produced. Benzyl in position-2 of harmine was reported to have significant contribution to the anti-proliferation effect of harmine derivatives [3, 8, 10, 20]. It should be noted that, possibly due to the steric hindrance of 2DG, benzyl cannot be modified on the position-2 of 2DG-Har-01 (the stereospecific blockade and demonstrated by our study). "
    [Show abstract] [Hide abstract] ABSTRACT: Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.
    Full-text · Article · Apr 2015 · Oncotarget
    Siwen Li Siwen Li Aqin Wang Aqin Wang Fan Gu Fan Gu +4 more authors... Zhaohui Wang Zhaohui Wang
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  • [Show abstract] [Hide abstract] ABSTRACT: A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(•) radical (IC50 ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
    Full-text · Article · Jun 2013 · European Journal of Medicinal Chemistry
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