Synthesis and Biological Evaluations of 1,2‐Diaryl Pyrroles as Analogues of Combretastatin A‐4

Jun, Sun Hee; Chen, Lei; Liu, Chunjiang; Wang, Zhan; Zuo, Daiying; Pan, Jiatong; Qi, Huan; Bao, Kai; Wu, Yingliang; Zhang, Weige

doi:10.1111/cbdd.12617

Cited by 19 publications

(9 citation statements)

References 28 publications

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“…This is consistent with what has been reported in the literature. Previous computational modeling of CA4 and analogues has revealed that predicted tubulin affinity correlates with in vitro cytotoxicity [ 41 – 43 ].…”

Section: Discussionmentioning

confidence: 99%

Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest

Tarade

Pignanelli

et al. 2017

PLoS ONE

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The cis-stilbene, combretastatin A4 (CA4), is a potent microtubule targeting and vascular damaging agent. Despite promising results at the pre-clinical level and extensive clinical evaluation, CA4 has yet to be approved for therapeutic use. One impediment to the development of CA4 is an inherent conformational instability about the ethylene linker, which joins two aromatic rings. We have previously published preliminary data regarding structurally simplified biphenyl derivatives of CA4, lacking an ethylene linker, which retain anti-proliferative and pro-apoptotic activity, albeit at higher doses. Our current study provides a more comprehensive evaluation regarding the anti-proliferative and pro-apoptotic properties of biphenyl CA4 derivatives in both 2D and 3D cancerous and non-cancerous cell models. Computational analysis has revealed that cytotoxicity of CA4 and biphenyl analogues correlates with predicted tubulin affinity. Additional mechanistic evaluation of the biphenyl derivatives found that their anti-cancer activity is dependent on prolonged mitotic arrest, in a similar manner to CA4. Lastly, we have shown that cancer cells deficient in the extrinsic pathway of apoptosis experience delayed cell death following treatment with CA4 or analogues. Biphenyl derivatives of CA4 represent structurally simplified analogues of CA4, which retain a similar mechanism of action. The biphenyl analogues warrant in vivo examination to evaluate their potential as vascular damaging agents.

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Section: Discussionmentioning

confidence: 99%

Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest

Tarade

Pignanelli

et al. 2017

PLoS ONE

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“…While the N-p-methoxybenzyl (PMB) analogue of compound 3a, corresponding to derivative 3b, was inactive both as an antiproliferative agent and as an inhibitor of tubulin assembly, the corresponding 4,5-dimethyl derivative 6 synthesized by Barker and co-workers exhibited remarkable activity, with an IC50 value of 0.07 and 0.21 M against the MDA-MB-231 breast cancer and K562 human leukemia cell lines, respectively [36]. Sun et al [37] reported a series of 1,2-diaryl pyrroles with the 3',4',5'-trimethoxyphenyl ring at the 2-position of the pyrrole ring. Among the tested compounds, the most active derivative was 7a, which effectively inhibited the growth of SGC-7901, HT-1080 and KB cancer cells, with IC50 values of 0.390, 0.070 and 0.045 μM, respectively.…”

Section: Introductionmentioning

confidence: 99%

A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Romagnoli

Oliva

Salvador

et al. 2021

European Journal of Medicinal Chemistry

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“…7 Two such nitrogen heterocyclic ring systems, maleimides and 3-pyrrolin-2-ones, have been studied in some detail. Polymethoxylated maleimides (e.g., 2), 8 3-pyrrolin-2-ones (e.g., 3), 9 and pyrroles (not shown) 10,11 have been investigated as cis-constrained analogs of the promising anti-cancer agent, combretastatin A-4. 12 SB-216763 (4) is an ATP-competitive inhibitor of glycogen synthase kinase.…”

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confidence: 99%

Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs

Mowery

Mejia

Franceschi

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity. This work provides a framework to better understand structure-activity relationships for inducing anti-proliferative activity in diaryl heterocyclic scaffolds.

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Synthesis and Biological Evaluations of 1,2‐Diaryl Pyrroles as Analogues of Combretastatin A‐4

Cited by 19 publications

References 28 publications

Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest

Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest

A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs

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