Design, synthesis and cytotoxic activities of naphthyl analogues of combretastatin A-4

Maya, Ana B.S.; Rey, Benedicto del; Clairac, Rafael Peláez Lamamié de; Caballero, Esther; Barasoaín, Isabel; Andreu, José Manuel; Medarde, Manuel

doi:10.1016/s0960-894x(00)00506-0

Cited by 37 publications

(32 citation statements)

References 7 publications

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“…The combretastatin acrylic acids chosen for synthesis were selected based on the biochemical activity available for the “parent” combretastatin analogues [ 52 ]—and which differed in structure only by the absence of the acrylic acid’s carboxylic acid functional group [ 22 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. By varying the benzaldehyde and phenylacetic acid in the Perkin condensation reaction, a series of combretastatin acrylic acid analogues 13 – 24 were prepared in yields of 36%–71% (see Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

et al. 2016

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Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

et al. 2016

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“…Compound 14, containing the 1-naphthyl substituent at C-4 of the benzoxepin scaffold, was found to have poor antiproliferative activity, with IC 50 = 25.9 μM. This compound could be considered as an analog of the known naphthylcombretastatins, in which the 1-naphthyl ring mimics the 3-hydroxy-4-methoxy ring B of combretastatin A4 33 . A possible explanation for the low activity of compound 14 is the steric hindrance caused by the presence of the 1-naphthyl substituent in the conformationally restricted benzoxepin analog, which hinders the required favorable aryl alignment predicted for ring B in the binding site.…”

Section: Biochemistrymentioning

confidence: 99%

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

Barrett

Carr

O’Boyle

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…These include various substituted phenyl rings 12 and other aromatic rings. 13 A few reports have attempted to modify the trimethoxy ring with mixed outcomes. For example, the m -methoxy group has been substituted by a fluoride to yield a similarly potent compound.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Pyridine-Bridged Analogues of Combretastatin-A4 as Anticancer Agents

et al. 2014

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A series of novel pyridine-bridged analogues of combretastatin-A4 (CA-4) were designed and synthesized. As expected, the 4-atom linker configuration retained little cytotoxicities in the compounds 2e, 3e, 3g, and 4i. Activities of the analogues with 3-atom linker varied widely depending on the phenyl ring substitutions, and the 3-atom linker containing nitrogen represents the more favorable linker structure. Among them, three analogues (4h, 4s, and 4t) potently inhibited cell survival and growth, arrested cell cycle, and blocked angiogenesis and vasculature formation in vivo in ways comparable to CA-4. The superposition of 4h and 4s in the colchicine-binding pocket of tubulin shows the binding posture of CA-4, 4h, and 4s are similar, as confirmed by the competitive binding assay where the ability of the ligands to replace tubulin-bound colchicine was measured. The binding data are consistent with the observed biological activities in antiproliferation and suppression of angiogenesis but are not predictive of their antitubulin polymerization activities.

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Design, synthesis and cytotoxic activities of naphthyl analogues of combretastatin A-4

Cited by 37 publications

References 7 publications

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

Design, Synthesis, and Biological Evaluation of Novel Pyridine-Bridged Analogues of Combretastatin-A4 as Anticancer Agents

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