Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors

Sun, Moran; Yu, Kunjie; Kang, Yingying; Qin, Jianwu; Zhang, Yixin; Duan, Yongtao; Wang, Long; Yao, Y. Lawrence

doi:10.1080/14756366.2021.2014831

Cited by 7 publications

(8 citation statements)

References 24 publications

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“…Furthermore, the in vitro results were then confirmed in vivo using a zebrafish embryo model [ 143 ]. Later, they also documented a similar antiangiogenic effect also for new α-fluorinated chalcone [ 144 ].…”

Section: Molecular and Cellular Mechanisms Of Actionmentioning

confidence: 85%

Chalcones and Gastrointestinal Cancers: Experimental Evidence

Michalková

Kello

Čižmáriková

et al. 2023

IJMS

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Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract cancers with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence or drug resistance and thus it is a great challenge to discover an effective and safe therapy for CRC and GC. In the last decade, numerous phytochemicals and their synthetic analogs have attracted attention due to their anticancer effect and low organ toxicity. Chalcones, plant-derived polyphenols, received marked attention due to their biological activities as well as for relatively easy structural manipulation and synthesis of new chalcone derivatives. In this study, we discuss the mechanisms by which chalcones in both in vitro and in vivo conditions suppress cancer cell proliferation or cancer formation.

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Section: Molecular and Cellular Mechanisms Of Actionmentioning

confidence: 85%

Chalcones and Gastrointestinal Cancers: Experimental Evidence

Michalková

Kello

Čižmáriková

et al. 2023

IJMS

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“…Values were expressed as percent change form control cultures grown with complete medium. 36 Standard dimensional parameters (percent area covered by HUVECs and total length of the HUVEC network per field) were noted, and standard topological parameters (number of meshes and branching points per field) were estimated.…”

Section: Experimental Partmentioning

confidence: 99%

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Yao

Huang

Wang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC 50 =25.6 µM, anti-angiogenesis in Zebrafish: IC 50 =38.4 µM, anti-proliferation against K562 and Jurkat: IC 50 =6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC 50 =4.8 µM and anti-angiogenesis in Zebrafish: IC 50 =3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC 50 = 0.09–1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

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“…On the basis of these findings, indole containing chalcone derivative 13 could be further investigated for anticancer drug discovery. [40] Twenty new indole-chalcone derivatives were synthesized, and their potential antiproliferative effects were tested against six human cancer cell lines. Derivatives with methoxy substitution at 4-position of indole (15) were found less active (IC 50 > 1 µM), while substitution of OMe group at 5-or 6-position resulted in significantly increased activity (16-18, Figure 3).…”

Section: Indole-chalcone Derivativesmentioning

confidence: 99%

“…series of phenstatin-based indole-linked chalcones(37)(38)(39)(40), were synthesized and assessed for their antiproliferative activity against various cancer cell lines. Among them, compound 37 exhibited notable antiproliferative effects on both oral squamous cancer cells and oral cancer stem-like spheroids.…”

mentioning

confidence: 99%

“…The pathohistological analysis using H&E staining of major organs, such as the liver and kidney, collected at the end of the in vivo study, revealed no apparent organ-related toxicities. Thus, these findings collectively indicate that compound 41 effectively inhibits the growth of melanoma tumors in vivo without causing evident toxicity.F I G U R E 9 Indole derivatives(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) as colchicine binding site inhibitors.…”

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confidence: 99%

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Indole derivatives targeting colchicine binding site as potential anticancer agents

Goel

Jaiswal

Jain

2023

Archiv der Pharmazie

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Microtubules are appealing as intracellular targets for anticancer activity due to their importance in cell division. Three important binding sites are present on the tubulin protein: taxane, vinca, and colchicine binding sites (CBS). Many USFDA‐approved drugs such as paclitaxel, ixabepilone, vinblastine, and combretastatin act by altering the dynamics of the microtubules. Additionally, a large number of compounds have been synthesized by medicinal chemists around the globe that target different tubulin binding sites. Although CBS inhibitors have proved their cytotoxic potential, no CBS‐targeting drug had been able to reach the market. Several studies have reported design, synthesis, and biological evaluation of indole derivatives as potential anticancer agents. These compounds have been shown to inhibit cancer cell proliferation, induce apoptosis, and disrupt microtubule formation. Moreover, the binding affinity of these compounds to the CBS has been demonstrated using molecular docking studies and competitive binding assays. The present work has reviewed indole derivatives as potential colchicine‐binding site inhibitors. The structure–activity relationship studies have revealed the crucial pharmacophoric features required for the potent and selective binding of indole derivatives to the CBS. The development of these compounds with improved efficacy and reduced toxicity could potentially lead to the development of novel and effective cancer therapies.

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Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors

Cited by 7 publications

References 24 publications

Chalcones and Gastrointestinal Cancers: Experimental Evidence

Chalcones and Gastrointestinal Cancers: Experimental Evidence

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Indole derivatives targeting colchicine binding site as potential anticancer agents

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