Oxazole‐Bridged Combretastatin A Analogues with Improved Anticancer Properties

Biersack, Bernhard; Effenberger, Katharina E.; Schobert, Rainer; Ocker, Matthias

doi:10.1002/cmdc.200900477

Cited by 21 publications

(10 citation statements)

References 15 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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“…The rationale of the design of active compounds was to retain the appropriate geometry of the two adjacent aryl groups required for potent bioactivity of chemically stable cis-restricted derivatives of CA-4. These were obtained by incorporating the olefinic double bond into vicinally diaryl-substituted fivemember aromatic heterocyclic rings (Table 1), such as pyrazole [67], imidazole [67][68][69], thiazole [70][71][72], furazan (1,2,5-oxadiazole) [73], furan [74,75], thiophene [76,77], isoxazole [78,79], oxazole [67,68,80,81], 1,2,3-thiadiazole [39], triazole [82,83,84,85], 1,2,3,4-tetrazole [70,86] and dioxolane [87]. Replacement of the olefinic bond with a five-member heterocyclic ring allowed the retention of the correct geometric orientation of the two phenyl rings of CA-4, placing them at an appropriate distance for efficient interaction with the colchicine-binding domain on tubulin [35].…”

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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“…[12] Many linkers that constrain the two phenyl rings to a similar cis-restricted conformation have been reported to increase the activity and stability of the designed compounds relative to CA4. This approach was mainly achieved by replacement of the double bond with other rigid linkers [13] or different cyclic moieties, [14] or by introducing another ring. [15] These considerations led us to design a new series of conformationally restricted CA4 analogues by inserting an additional ring between the cis-olefinic bond and one of the aromatic moieties of the CA4 structure.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

et al. 2011

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A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.

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Oxazole‐Bridged Combretastatin A Analogues with Improved Anticancer Properties

Cited by 21 publications

References 15 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

Tubulin-interactive stilbene derivatives as anticancer agents

Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

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