Combretastatin A-4 derived 5-(1-methyl-4-phenyl-imidazol-5-yl)indoles with superior cytotoxic and anti-vascular effects on chemoresistant cancer cells and tumors

Mahal, Katharina; Biersack, Bernhard; Schruefer, Sebastian; Resch, Marcus; Ficner, Ralf; Schobert, Rainer; Mueller, Thomas

doi:10.1016/j.ejmech.2016.04.045

Cited by 31 publications

(20 citation statements)

References 35 publications

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“…Several structural modifications of the CA-4 pharmacophore have subsequently been undertaken to overcome this disadvantage, e.g. replacing the cis double bond with a heterocycle, oxadiazole, isoxazole and imidazole, resulting in compounds, such as 1, 2 and 3 respectively (Figure 1) [27][28][29][30][31][32] . In this work, we undertook a rational design approach of introducing chalcone system (ring C) in the form of either oxazolone or imidazolone between the two rings A and B, as well as isosterically replace ring B with quinolone.…”

Section: Design and Chemistrymentioning

confidence: 99%

“…Unfortunately, the cis configuration of CA-4 has a propensity for undergoing transformation to the inactive trans configuration upon storage and during in vivo metabolism. To overcome this, many structural modifications of CA-4 have been undertaken where the cis double bond is replaced with heterocycles, either monocyclic, such as oxadiazole, isoxazole and imidazole, resulting in compounds, such as 1, 2 and 3 respectively (Figure 1) [27][28][29][30][31][32][33] or fused heterocyclic, such as pyrazolopyridines 34 , triazolopyridines 35 and triazolothiadiazine derivatives 36 . These compounds, like CA-4 showed pronounced activity against a panel of cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

Ibrahim

Hawwas

Malebari

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC 50 ranging from 0.010 to 0.042 mM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G 2 /M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer. HIGHLIGHTS A novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised. Compound 12c showed significant antiproliferative activities against different cancer cell lines. Compound 12c effectively inhibited tubulin polymerisation and competed with [ 3 H] colchicine in binding to tubulin. Compound 12c arrested the cell cycle at G 2 /M phase, effectively inducing apoptosis and inhibition of cell migration.

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Section: Design and Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

Ibrahim

Hawwas

Malebari

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Nowadays, there are increasing numbers of chemoresistant cancers to diverse chemotherapeutic drugs, while these drugs induce undesirable to severe side effects when used at their then required prolonged or high dose usage [14]. Thus, it is important to find an alternative agent, especially from natural products including propolis.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of cardol, isolated from Trigona incisa stingless bee propolis, induced apoptosis in the SW620 human colorectal cancer cell line

Kustiawan

Lirdprapamongkol

Palaga

et al. 2017

BMC Pharmacol Toxicol

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BackgroundCardol is a major bioactive constituent in the Trigona incisa propolis from Indonesia, with a strong in vitro antiproliferative activity against the SW620 colorectal adenocarcinoma cell line (IC50 of 4.51 ± 0.76 μg/mL). Cardol induced G0/G1 cell cycle arrest and apoptotic cell death. The present study was designed to reveal the mechanism of cardol’s antiproliferative effect and induction of apoptosis.MethodsChanges in cell morphology were observed by light microscopy. To determine whether the mitochondrial apoptotic pathway was involved in cell death, caspase-3 and caspase-9 activities, western blot analysis, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) levels were assayed.ResultsChanges in the cell morphology and the significantly increased caspase-3 and caspase-9 activities, plus the cleavage of pro-caspase-3, pro-caspase-9 and PARP, supported that cardol caused apoptosis in SW620 cells within 2 h after treatment by cardol. In addition, cardol decreased the mitochondrial membrane potential while increasing the intracellular ROS levels in a time- and dose-dependent manner. Antioxidant treatment supported that the cardol-induced cell death was dependent on ROS production.ConclusionCardol induced cell death in SW620 cells was mediated by oxidative stress elevation and the mitochondrial apoptotic pathway, and these could be the potential molecular mechanism for the antiproliferative effect of cardol.

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“…Of course, pyrrole is not the only azaheterocyclic scaffold used to prepare combretastatin analogues. Literature research indicates oxazole, indazole, or thiophene derivatives [151,[154][155][156][157]. Stefanski et al found that N-methylimidazole-bridged CA-4 analogues were significantly less active than their corresponding oxazole analogues (Figure 7, Table 2) [151].…”

Section: Modifications Related To the Methylene Bridge-change With Cymentioning

confidence: 99%

More Than Resveratrol: New Insights into Stilbene-Based Compounds

et al. 2020

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The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant “drug-likeness” scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the “fresh outlook” about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.

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Combretastatin A-4 derived 5-(1-methyl-4-phenyl-imidazol-5-yl)indoles with superior cytotoxic and anti-vascular effects on chemoresistant cancer cells and tumors

Cited by 31 publications

References 35 publications

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

Molecular mechanism of cardol, isolated from Trigona incisa stingless bee propolis, induced apoptosis in the SW620 human colorectal cancer cell line

More Than Resveratrol: New Insights into Stilbene-Based Compounds

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