3D-QSAR Study of Combretastatin A-4 Analogs Based on Molecular Docking

Ye, Jin; Pan, Qi; Wang, Zhiwei; Shen, Qirong; Wang, Jian; Zhang, Weige; Song, Haiyan

doi:10.3390/molecules16086684

Cited by 25 publications

(13 citation statements)

References 36 publications

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“…The optimized geometries and natural charges calculated for non-hydrogen atoms are almost identical with the exception of the nitrogens on the azo bridge. Because the aromatic groups and their methoxy substituents are the major contributors to tubulin binding in CA4, 33 based on structure alone, we would expect that Azo-CA4 would be a potent tubulin inhibitor and act similarly to CA4.…”

Section: Resultsmentioning

confidence: 99%

Photoswitchable anticancer activity via trans–cis isomerization of a combretastatin A-4 analog

et al. 2016

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Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13–35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Photoswitchable anticancer activity via trans–cis isomerization of a combretastatin A-4 analog

et al. 2016

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“…CA-4 and its water-soluble prodrugs such as CA-4P (fosbretabulin and zybrestat) [4] and AVE8062 (ombrabulin) [5] have entered clinical trials for the treatment of anaplastic thyroid cancer and other solid tumors in both USA and Europe [6]. Due to its small molecular weight and simple structure, an impressive number of synthetic research was carried out over the past decades [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

Song

Wang

et al. 2020

IJMS

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Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

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“…6 Several structure-activity relationship studies of CA-4 has revealed that the cis configuration of the double bond, the 3,4,5-trimethoxy groups on the A-ring, and the meta-hydroxy and para-methoxy groups on the B-ring are fundamental for its main biological activity. 7 Thereby, CA-4 has inspired the synthesis and biological evaluation of different cytotoxic analogues containing these privileged pharmacophores: the disodium phosphate prodrug CA-4P 2, 8 colchicine 3, 9 podophyllotoxin 4, 10 eugenol 5 11 and some oxindole derivatives 6-7 12 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Combretastatin A-4: The Antitubulin Agent that Inspired the Design and Synthesis of Styrene and Spiroisatin Hybrids as Promising Cytotoxic, Antifungal and Antiviral Compounds

Brand

Kouznetsov

Puerto

et al. 2020

J. Braz. Chem. Soc.

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The design of a series of styrene and spiroisatin hybrids was based on the structure of combretastatin A-4 1. This library of 20 compounds were synthesized with the pharmacophoric units: 3,4,5-trimethoxy or/and 4-hydroxy-3-methoxy phenyl moities in their structure. Thereby, the libraries of β-nitrostyrenes 10a-10c, spiroisatin-dihydroquinolines 14a-14c, spiroisatinthiazolidinones 17a-17c and spiroisatin-nitropyrrolizidines 20a-20k were evaluated for their in vitro cytotoxic, anti-proliferative, antifungal and antiviral activities. Biological results revealed that among these compounds, β-nitrostyrenes 10a-10c exhibited significant cytotoxicity (HeLa and Jurkat tumor cells) and antifungal (T. mentagrophytes) activities. Moreover, the spiroisatindihydroquinoline 14a and 14c showed promising cytotoxicity (U937 cells). 14a-14c molecules were active against human herpesviruses serotypes 1 and 2 (HHV-1 and HHV-2), but only 14a and 14b were effective against dengue virus serotype 2 (DENV-2). The spiroisatin-nitropyrrolizidine 20c exhibited moderate anti-herpetic activity, while 17c spiroisatin-thiazolidinone derivative also reduced the infection of HHV-1 and DENV-2. Finally, the molecular docking showed that these kind of molecules interact with the subunit α/β-tubulin.

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3D-QSAR Study of Combretastatin A-4 Analogs Based on Molecular Docking

Cited by 25 publications

References 36 publications

Photoswitchable anticancer activity via trans–cis isomerization of a combretastatin A-4 analog

Photoswitchable anticancer activity via trans–cis isomerization of a combretastatin A-4 analog

Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

Combretastatin A-4: The Antitubulin Agent that Inspired the Design and Synthesis of Styrene and Spiroisatin Hybrids as Promising Cytotoxic, Antifungal and Antiviral Compounds

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