Novel cyanocombretastatins as potent tubulin polymerisation inhibitors

Jalily, Pouria H.; Hadfield, John A.; Hirst, Nicholas; Rossington, Steven B.

doi:10.1016/j.bmcl.2012.08.089

Cited by 12 publications

(6 citation statements)

References 29 publications

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“…Combretastatin is an anticancer drug based on the chemical structure stilbene. It binds to the β‐tubulin subunit in the cytoskeleton and inhibits microtubule polymerization (Jalily et al ., ). The lower activity E ‐isomers of the anticancer combretastatin drugs are naturally fluorescent and their uptake and cellular distribution has been studied by FLIM (Bisby et al ., ) in connection with their possible use as photo‐activated prodrugs (Scherer et al ., ).…”

Section: Resultsmentioning

confidence: 97%

A series of flexible design adaptations to the Nikon E‐C1 and E‐C2 confocal microscope systems for UV, multiphoton and FLIM imaging

Botchway

Scherer

Hook

et al. 2015

Journal of Microscopy

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Multiphoton microscopy is widely employed in the life sciences using extrinsic fluorescence of low- and high-molecular weight labels with excitation and emission spectra in the visible and near infrared regions. For imaging of intrinsic and extrinsic fluorophores with excitation spectra in the ultraviolet region, multiphoton excitation with one- or two-colour lasers avoids the need for ultraviolet-transmitting excitation optics and has advantages in terms of optical penetration in the sample and reduced phototoxicity. Excitation and detection of ultraviolet emission around 300 nm and below in a typical inverted confocal microscope is more difficult and requires the use of expensive quartz optics including the objective. In this technical note we describe the adaptation of a commercial confocal microscope (Nikon, Japan E-C1 or E-C2) for versatile use with Ti-sapphire and OPO laser sources and the addition of a second detection channel that enables detection of ultraviolet fluorescence and increases detection sensitivity in a typical fluorescence lifetime imaging microscopy experiment. Results from some experiments with this setup illustrate the resulting capabilities.

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Section: Resultsmentioning

confidence: 97%

A series of flexible design adaptations to the Nikon E‐C1 and E‐C2 confocal microscope systems for UV, multiphoton and FLIM imaging

Botchway

Scherer

Hook

et al. 2015

Journal of Microscopy

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“…Also, analogues containing a 3,4,5-trimethoxyphenyl group generally exhibited better growth inhibition properties than analogues containing a 3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl moiety. Importantly, introduction of a 2-benzo[ b ]thiophenyl or 2-indolyl heterocyclic moiety in place of the 3-fluoro-4-methoxyphenyl moiety of trans -cyano CA-4 [9] (Fig. 1, III) dramatically improved anti-cancer activity.…”

Section: Resultsmentioning

confidence: 99%

“…Structurally related cyanocombretastatin analogues [8, 9] (Fig. 1, III) and similar analogues that incorporate different heterocyclic moieties, such as indole, benzothiophene, quinoline and quinazoline have also been reported as cytotoxic compounds, and are potent inhibitors of tubulin polymerization potencies comparable to that of CA-4 [10–13].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Penthala

Zong

Ketkar

et al. 2015

European Journal of Medicinal Chemistry

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A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs.

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“…1-3a ) have focused on the construction of bridge units between the two aromatic ring systems to overcome the instability of the molecules due to cis, trans -isomerization in solution. 1-5 Diverse biological activities have been documented for drug molecules that incorporate the triazole ring system, including anti-cancer, 6-8 anti-bacterial, 9 anti-fungal 10 and anti-convulsant activities. 11 Recently, we reported the synthesis of a variety of heterocyclic cyanstilbene analogs as anti-cancer agents.…”

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confidence: 99%

l-Proline catalyzed one-step synthesis of 4,5-diaryl-2H-1,2,3-triazoles from heteroaryl cyanostilbenes via [3+2]cycloaddition of azide

Penthala

Madadi

Janganati

et al. 2014

Tetrahedron Letters

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Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a-i and 9a-e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan and indole, catalyzed by L-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple and environmentally benign procedure that affords good yields and relatively short reaction times.

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Novel cyanocombretastatins as potent tubulin polymerisation inhibitors

Cited by 12 publications

References 29 publications

A series of flexible design adaptations to the Nikon E‐C1 and E‐C2 confocal microscope systems for UV, multiphoton and FLIM imaging

A series of flexible design adaptations to the Nikon E‐C1 and E‐C2 confocal microscope systems for UV, multiphoton and FLIM imaging

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

l-Proline catalyzed one-step synthesis of 4,5-diaryl-2H-1,2,3-triazoles from heteroaryl cyanostilbenes via [3+2]cycloaddition of azide

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