2005
DOI: 10.1021/jm049622b
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Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-Inducing Activity in HL60 and in MDR Cell Lines

Abstract: Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC50 < 1 microM) and apoptosis-inducing activity but poor antitubulin acti… Show more

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Cited by 147 publications
(102 citation statements)
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“…7 On the other hand, there is a limited number of analogs where the stilbene core of CA-4 has been replaced with 1,3-substituted heterocycles. Examples of heterocyclic bridges include isoxazolines, 8 oxadiazolines, 9 and pyrazoles. 10 In our efforts to discover new potential anti-cancer CA-4 based chemotherapeutic agents, 11 we decided to explore series of 3,5-diaryl-4,5-dihydropyrazole compounds bearing a 3,4,5-trimethoxyphenyl moiety as the prerequisite for potent cytotoxicity, 6d combined with a variety of substituted phenyl rings, while the ethenyl bridge in the CA-4 skeleton was replaced with a structurally flexible non-aromatic nitrogen heterocycle which would augment biological solubility.…”
Section: Introductionmentioning
confidence: 99%
“…7 On the other hand, there is a limited number of analogs where the stilbene core of CA-4 has been replaced with 1,3-substituted heterocycles. Examples of heterocyclic bridges include isoxazolines, 8 oxadiazolines, 9 and pyrazoles. 10 In our efforts to discover new potential anti-cancer CA-4 based chemotherapeutic agents, 11 we decided to explore series of 3,5-diaryl-4,5-dihydropyrazole compounds bearing a 3,4,5-trimethoxyphenyl moiety as the prerequisite for potent cytotoxicity, 6d combined with a variety of substituted phenyl rings, while the ethenyl bridge in the CA-4 skeleton was replaced with a structurally flexible non-aromatic nitrogen heterocycle which would augment biological solubility.…”
Section: Introductionmentioning
confidence: 99%
“…This mostly included either modification of the olefinic bond by the introduction of saturation, substituents and other functionalities or its replacement with a three to six membered ring system, which resulted in cis restricted analogues of CA4. 16,[19][20][21][22] Similar to CA4, a number of colchicine site binding ligands are known to inhibit tubulin polymerization and are considered as potential lead like molecules. One of them, E7010 is the first orally active antimitotic sulphonamide derivative that has received much interest in recent years and currently it is in clinical trials.…”
mentioning
confidence: 99%
“…These cell lines were chosen as they have shown previous susceptibility to CA-4. 2,6,12,21,22 The results show that 2,3-diaryl pyrroles 34 and 35 were more active than the prepared1,2-diaryl pyrroles. The most active compound 35 had IC 50 values of 0.21 lM and 0.07 lM against K-562 and MDA-MB-231 cell lines respectively.…”
mentioning
confidence: 94%