Synthesis, antiproliferative and antibacterial evaluation of C-ring modified colchicine analogues

Huczyński, Adam; Rutkowski, Jacek; Popiel, Katarzyna; Maj, Ewa; Wietrzyk, Joanna; Stefańska, Joanna; Majcher, Urszula; Bartl, Franz

doi:10.1016/j.ejmech.2014.11.037

Cited by 30 publications

(21 citation statements)

References 20 publications

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“…Although sterically limited due to the structure of the colchicine‐binding site, the most prominent position for introducing structural alterations is the 10‐methoxy group situated in ring C. Replacements at this position and the amino group at position 7 resulted in compounds with similar or lower cytotoxicity as that of colchicine and higher selectivity of action toward specific cells, such as cancer cells . Particularly promising is the replacement of the 10‐methoxy group by amine‐containing scaffolds such as amino acids, or ammonia .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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Recent studies indicate that tubulin can be a host factor for vector‐borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub‐micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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“…epidermidis . They reported an MIC range of 32 – 256 μg ml −1 compared to those of ciprofloxacin (0.125 – 64 μg ml −1 ) …”

Section: Resultsmentioning

confidence: 99%

“…They reported an MIC range of 32 -256 lg ml À1 compared to those of ciprofloxacin (0.125 -64 lg ml À1 ). [37] Conclusions To sum up, 48 new aldimine-type Schiff base bearing 3,4,5-trimethoxyphenyl ring and 1,2,4-triazole-3-thiol/ thione were designed and the best compounds according to the obtained results of the molecular docking study on tubulin complex (PDB code: 1SA0) were synthesized, and evaluated for cytotoxicity, antitubulin and antimicrobial activities. 4-nitro substituted compound was introduced as the best compound in all applied biological assay and inhibited polymerization of tubulin at concentration of 5 lM.…”

Section: Biological Activitymentioning

confidence: 99%

Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

Ameri

Khodarahmi

Forootanfar

et al. 2018

Chemistry & Biodiversity

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A series of hybrid aldimine-type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4-triazole-3-thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4-nitro, 2-nitro, 3-nitro, 4-Cl-3-nitro, and 4-Me N) on the aldehyde ring were the best compounds with remarkable binding energies (-9.09, -9.07, -8.63, -8.11, and -8.07 kcal mol , respectively) compared to colchicine (-8.12 kcal mol ). These compounds were also showed remarkable binding energies from -10.66 to -9.79 and -10.12 to -8.95 kcal mol on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF-7, and A549 cancer cell lines indicated that 4-nitro and 2-nitro substituted compounds were the most effective agents by mean IC values of 11.84 ± 1.01 and 19.92 ± 1.36 μm, respectively. 4-Nitro substituted compound (5 μm) and 2-nitro substituted compound (30 μm) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm) and 4-nitro substituted compound displayed IC values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm). This compound also showed the lowest MIC values on all tested microbial strains including three Gram-positive, four Gram-negative, and three yeast pathogens.

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“…It was clearly proven that chemical modification of SAL and other polyether ionophores may not only increase the biological activity of resulting derivatives but also reduce their general toxicity [18][19][20][21]. Furthermore, SAL with a modified C1 carboxyl group (amides or esters) transports cations by a biomimetic mechanism, while chemically unmodified SAL transports cations through biological membranes via an electroneutral mechanism [22,23].…”

Section: In Vitro Activity Of Cytotoxic Drugs Salinomycin and Its Dmentioning

confidence: 99%

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

et al. 2020

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Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.

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Synthesis, antiproliferative and antibacterial evaluation of C-ring modified colchicine analogues

Cited by 30 publications

References 20 publications

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

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