- Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring
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Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure-activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa-Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9-methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.
- LoRe, Daniele,Zhou, Ying,Mucha, Joanna,Jones, Leigh F.,Leahy, Lorraine,Santocanale, Corrado,Krol, Magdalena,Murphy, Paul V.
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- Total syntheses and biological reassessment of lactimidomycin, isomigrastatin and congener glutarimide antibiotics
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Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage. On the contrary! Alkyne metathesis powered a synthesis-driven (re)evaluation of bipartite glutarimide antibiotics, including lactimidomycin and isomigrastatin, which feature highly strained polyunsaturated macrolide head groups. Rather than being potent cell migration inhibitors as previously claimed, lactimidomycin and progeny were found to be acutely cytotoxic, causing cell death before any specific interference with cell motility could set in. Copyright
- Micoine, Kévin,Persich, Peter,Llaveria, Josep,Lam, My-Hanh,Maderna, Andreas,Loganzo, Frank,Fürstner, Alois
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supporting information
p. 7370 - 7383
(2013/07/25)
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- Synthesis and antiviral activities of synthetic glutarimide derivatives
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A series of novel glutarimide compounds were synthesized and their antiviral activities were evaluated. The compounds displaying the strongest antiviral activities included 5, 6f, 7e and 9 against coxsackievirus B3 (Cox B3), 10 and 6f against influenza vi
- Ji, Xing-Yue,Zhong, Zhao-Jin,Xue, Si-Tu,Meng, Shuai,He, Wei-Ying,Gao, Rong-Mei,Li, Yu-Huan,Li, Zhuo-Rong
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experimental part
p. 1436 - 1441
(2010/12/25)
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- Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-κB
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Synthesis of 9-methylstreptimidone analogs and their inhibitory activities against NF-κB (nuclear factor-κB) are reported. Among several active derivatives synthesized in this study, 8 with a relatively simple structure, exhibited inhibitory activity agai
- Ishikawa, Yuichi,Tachibana, Miyuki,Matsui, Chino,Obata, Rika,Umezawa, Kazuo,Nishiyama, Shigeru
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scheme or table
p. 1726 - 1728
(2009/11/30)
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- MIGRASTATIN ANALOG COMPOSITIONS AND USES THEREOF
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In one aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of general formula (I), wherein R1-R6, Ra-RC, Q, Y1, Y2 and n are as defined herein, whereby the composition is formulated for administration to a subject at a dosage between about 0.1 mg/kg to about 50 mg/kg of body weight. In another aspect, the present invention provides a method for treating breast tumor metastasis in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the inventive composition described directly above and a pharmaceutically acceptable carrier, adjuvant or vehicle.
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