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The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis

Gaul, Christoph ; Njardarson, Jón T ; Shan, Dandan ; Dorn, David C ; Wu, Kai-Da ; Tong, William P ; Huang, Xin-Yun ; Moore, Malcolm A. S ; Danishefsky, Samuel J

Journal of the American Chemical Society, 2004-09, Vol.126 (36), p.11326-11337 [Peer Reviewed Journal]

Washington, DC: American Chemical Society

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Title:
The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis
Author: Gaul, Christoph ; Njardarson, Jón T ; Shan, Dandan ; Dorn, David C ; Wu, Kai-Da ; Tong, William P ; Huang, Xin-Yun ; Moore, Malcolm A. S ; Danishefsky, Samuel J
Subjects: Alcohols - chemical synthesis ; Alcohols - pharmacology ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Movement - drug effects ; Chemistry ; Chemotherapy ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives ; Humans ; Ketones - chemical synthesis ; Ketones - pharmacology ; Lactones - chemical synthesis ; Lactones - pharmacology ; Macrolides - chemical synthesis ; Macrolides - pharmacology ; Mammary Neoplasms, Experimental - drug therapy ; Mammary Neoplasms, Experimental - pathology ; Medical sciences ; Mice ; Organic chemistry ; Pharmacology. Drug treatments ; Piperidones - chemical synthesis ; Piperidones - chemistry ; Piperidones - pharmacology ; Preparations and properties ; Structure-Activity Relationship
Is Part Of: Journal of the American Chemical Society, 2004-09, Vol.126 (36), p.11326-11337
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Description: The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with anti-metastatic properties, has been accomplished. Our concise and flexible approach utilized a Lewis acid-catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin (2 + 3 → 21). Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain was achieved by an anti-selective aldol addition of propionyl oxazolidinone 28 to angelic aldehyde 27, followed by a Horner−Wadsworth−Emmons (HWE) coupling of 32 with glutarimide aldehyde 5. Finally, the assembly of the macrocycle was realized by a highly (E)-selective ring-closing metathesis (35 → 37). Utilizing the power of diverted total synthesis (DTS), a series of otherwise inaccessible analogues was prepared and evaluated for their potential as tumor cell migration inhibitors in several in vitro assays. These studies revealed a dramatic increase in activity when the natural motif was considerably simplified, presenting macrolactones 45 and 48, as well as macrolactam 55, macroketone 60, and CF3-alcohol 71 as promising anti-metastatic agents.
Publisher: Washington, DC: American Chemical Society
Language: English

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The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis

Gaul, Christoph ; Njardarson, Jón T ; Shan, Dandan ; Dorn, David C ; Wu, Kai-Da ; Tong, William P ; Huang, Xin-Yun ; Moore, Malcolm A. S ; Danishefsky, Samuel J

Washington, DC: American Chemical Society

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