The migrastatin family: Discovery of potent cell migration inhibitors by chemical synthesis Journal Article
| Authors: | Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K. D.; Tong, W. P.; Huang, X. Y.; Moore, M. A. S.; Danishefsky, S. J. |
| Article Title: | The migrastatin family: Discovery of potent cell migration inhibitors by chemical synthesis |
| Abstract: | The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with antimetastatic 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. |
| Keywords: | unclassified drug; solid tumor; animals; mice; cell death; tissue regeneration; drug potency; structure-activity relationship; wound healing; endothelium, vascular; tumors; cell migration; cell movement; catalysis; natural product; macrolide; lewis acid; synthesis; synthesis (chemical); ring closing metathesis; stereochemistry; assays; ketones; macrocyclic compound; mammary neoplasms, experimental; lactones; condensation; cells; natural products; migrastatin; macrolides; piperidones; antimetastatic agent; alcohols; humans; article; antimetastatic properties; leukocyte migration inhibition test |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 126 |
| Issue: | 36 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2004-09-15 |
| Start Page: | 11326 |
| End Page: | 11337 |
| Language: | English |
| DOI: | 10.1021/ja048779q |
| PROVIDER: | scopus |
| PUBMED: | 15355116 |
| DOI/URL: | |
| Notes: | J. Am. Chem. Soc. -- Cited By (since 1996):96 -- Export Date: 16 June 2014 -- CODEN: JACSA -- Source: Scopus |
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