The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis.
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 CF(3)-alcohol 71 as promising anti-metastatic agents.
Gaul
Christoph
C
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Njardarson
Jón T
JT
Shan
Dandan
D
Dorn
David C
DC
Wu
Kai-Da
KD
Tong
William P
WP
Huang
Xin-Yun
XY
Moore
Malcolm A S
MA
Danishefsky
Samuel J
SJ
D000438:Alcohols / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000438:Alcohols; D007659:Ketones; D007783:Lactones; D018942:Macrolides; D010881:Piperidones; C418199:migrastatin; C007864:glutarimide