<i>Iso</i>combretastatins A versus Combretastatins A: The Forgotten <i>iso</i>CA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agent

Messaoudi, Samir; Tréguier, Bret; Hamzé, Abdallah; Provot, Olivier; Peyrat, Jean-François; Losada, Jordi Rodrigo De; Liu, Jian‐Miao; Bignon, Jérôme; Wdzieczak‐Bakala, Joanna; Thoret, Sylviane; Dubois, Joëlle; Brion, Jean‐Daniel; Alami, Mouâd

doi:10.1021/jm900321u

Cited by 237 publications

(127 citation statements)

References 26 publications

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“…[12][13][14][15] Our strategy in the field of CA-4 research is focusedo nr eplacement of the unstable Z-double bond with severall inkers [16,17] of various sizes, from which the one-atom linker was found to produce the optimal length between the two aromaticr ings Aa nd B. These studies revealed novel promising classes of non-isomerizable CA-4 analogues, [17] including 1,1-diarylethylenes 1, [18,19] 1,1-diarylethanes 2, [20] and azaisoerianin derivatives 3 [21] ( Figure 1). Thus, we have demonstrated that it is possible to replacet he Z-1,2-diarylethylene scaffold of CA-4 with 1,1-diarylethylene to give isoCA-4, as tructural isomer of CA-4, with biological activities similar to those of the natural product.…”

Section: Combretastatinmentioning

confidence: 99%

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

et al. 2015

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A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4 b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4 c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH2 CA-4, are able to arrest HCT116 cancer cells in the G2 /M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.

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Section: Combretastatinmentioning

confidence: 99%

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

et al. 2015

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“…Im Zusammenhang mit der Synthese von Isocombretastatin-Analoga [24] optimierten Alami et al die Kreuzkupplungsreaktion der polysubstituierten Acetophenonhydrazone 29 mit Aryltriflaten 30. Die katalytischen Bedingungen entsprechen etwa den Standardbedingungen für Reaktionen mit Halogeniden, außer dass größere Mengen an Katalysator benötigt werden.…”

Section: Kupplungen Mit Arylsulfonatenunclassified

Tosylhydrazone – neue Anwendungen klassischer Reagentien in palladiumkatalysierten Kreuzkupplungen und metallfreien Umsetzungen

2011

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Tosylhydrazone sind wertvolle Zwischenverbindungen, die in der organischen Chemie seit fast 60 Jahren Anwendung finden. Die jüngste Entdeckung einer palladiumkatalysierten Kreuzkupplungsreaktion unter Beteiligung eines Tosylhydrazon‐Kupplungspartners weckte ein neues Interesse an diesen Reagentien. Die Reaktion ist nahezu universell für Hydrazone und kann zur Synthese polysubstituierter Alkene genutzt werden. Im Verlauf dieser Forschungen wurden außerdem neue metallfreie C‐C‐ und C‐O‐Kupplungen gefunden. Da Tosylhydrazone leicht aus Carbonylverbindungen zugänglich sind, bieten diese Umwandlungen neue Möglichkeiten für die Derivatisierung von Carbonylverbindungen. Dieser Kurzaufsatz behandelt diese neuartigen Reaktionen dieses klassischen Reagens.

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“…The structure-activity relationships of CA-4 have been extensively studied, and >28,000 derivatives and analogs have been synthesized and biologically evaluated to date [20]. The chemical structure of CA-4 is usually partitioned into three main moieties, namely the trimethoxyphenyl group (ring A), a methoxylated phenolic moiety (ring B) and the ethenyl bridge linking rings A and B (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

Fortin¹,

Wei²,

Kotra³

et al. 2015

OJMC

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Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the * Corresponding author. S. Fortin et al. 10C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

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Isocombretastatins A versus Combretastatins A: The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agent

Cited by 237 publications

References 26 publications

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

Tosylhydrazone – neue Anwendungen klassischer Reagentien in palladiumkatalysierten Kreuzkupplungen und metallfreien Umsetzungen

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

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