Synthesis and Biological Evaluation of Colchicine B-Ring Analogues Tethered with Halogenated Benzyl Moieties

Cosentino, Laura; Redondo‐Horcajo, Mariano; Zhao, Ying; Santos, Ana Rita; Chowdury, Kaniz F.; Vinader, V.; Abdallah, Qasem; Abdel‐Rahman, Hamdy M.; Fournier-Dit-Chabert, Jérémie; Shnyder, Steve D.; Loadman, Paul M.; Fang, Wei‐Shuo; Díaz, J. Fernando; Barasoaín, Isabel; Burns, Philip A.; Pors, Klaus

doi:10.1021/jm301151t

Cited by 28 publications

(22 citation statements)

References 28 publications

(54 reference statements)

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“…Hydrolysis of these esters with LiOH gave the corresponding carboxylic acids. Subsequent amidation of these intermediates with de-Accolchicine [36,37] afforded compounds 5aed. Finally, treatment of these compounds with TFA gave the target molecules 6aed.…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Zhang

Kong

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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Section: Chemistrymentioning

confidence: 99%

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Zhang

Kong

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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“…Numerous modified colchicine and thiocolchicine derivatives with substituted benzyl moieties at carbon C7 have been synthesized and their biological activity has been evaluated. Some of the described derivatives showed antiproliferative activity superior to that of colchicine [ 22 , 30 ]. In addition, as shown in our earlier studies, the replacement of -OCH 3 group at position C10 with -NHCH 3 group leads to generation of compounds more active than unmodified colchicine [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking

et al. 2020

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Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications at C7 (carbon-nitrogen single bond) and C10 (methylamino group) positions. All the obtained compounds have been tested in vitro to determine their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. The majority of obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin and cisplatin against the tested cancerous cell lines. Additionally, most of the presented derivatives were able to overcome the resistance of LoVo/DX cells. Additionally, their mode of binding to β-tubulin was evaluated in silico. Molecular docking studies showed that apart from the initial amides 1 and 2, compound 14, which had the best antiproliferative activity (IC50 = 0.1–1.6 nM), stood out also in terms of its predicted binding energy and probably binds best into the active site of βI-tubulin isotype.

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“…Interestingly, colchicine also potently blocked the labeling and enrichment of tubulin, and these results raised two possibilities: 1) Nap‐2 and other Mcl‐1 inhibitors share the same binding site with colchicine, or 2) depolymerization of microtubules caused by colchicine makes Nap‐2 dissociate from microtubules; this led to the idea that Nap‐2 might preferentially associate with microtubules rather than tubulin subunits.…”

Section: Resultsmentioning

confidence: 99%

Proteome‐Wide Identification of On‐ and Off‐Targets of Bcl‐2 Inhibitors in Native Biological Systems by Using Affinity‐Based Probes (AfBPs)

et al. 2018

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Selective inhibition of proteins of the Bcl-2 family by small-molecule inhibitors is a promising new approach in drug discovery. However, information about how these molecules interact with their cellular targets (on- and off-) is highly limited. We have designed and synthesized photoreactive and "clickable" affinity-based probes (AfBPs)-Nap-2 and Nap-5-by introducing photo-crosslinkers onto Nap-1, a fluorescent derivative of small-molecule Bcl-2 inhibitor S1-6. The resulting trifunctional probes Nap-2 and Nap-5 can enrich, visualize, and enable the identification of cellular on- and off-targets of Bcl-2 inhibitors both in vitro and in situ. Tubulin was validated as an off-target of Bcl-2 inhibitors (Nap-1 and S1-6) by large-scale cell-based proteome profiling and pull-down/western blotting (PD/WB) with Nap-2 and Nap-5. It was preliminarily illustrated to be a BH3-containing protein because some well-known Bcl-2 inhibitors can block the labeling of tubulin by Nap-2.

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Synthesis and Biological Evaluation of Colchicine B-Ring Analogues Tethered with Halogenated Benzyl Moieties

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Cited by 28 publications

References 28 publications

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking

Proteome‐Wide Identification of On‐ and Off‐Targets of Bcl‐2 Inhibitors in Native Biological Systems by Using Affinity‐Based Probes (AfBPs)

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