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Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity.

Abstract
The semi-synthetic lignan terameprocol inhibits the transcription of several inflammatory and oncogenic genes and has been evaluated for its anti-cancer properties. Here we investigated the effect of restricting the flexibility of the carbon linker connecting the terminal rings of terameprocol on its growth inhibitory activity. Conformational restriction was explored by introducing unsaturation, inserting polar entities with limited flexibility and cyclization of the connecting linker. Twenty three compounds were synthesized and evaluated on a panel of malignant human cells. The most promising compounds were those with non-polar linkers, as seen in butadiene 1a and the cyclized benzylideneindane analog 7. Both compounds were more potent than terameprocol on pancreatic BxPC-3 cells with GI50 values of 3.4 and 8.1 μM, respectively. Selected isomers of 1a (E,E) and 7 (Z) adopted low energy bent conformations that mimicked the low energy conformer of terameprocol. It is tempting to propose that conformational similarity to terameprocol may have contributed to their good activity. The scaffolds of 1a and 7 should be further investigated for their anticancer potential.
AuthorsSherman Si Han Ho, Mei Lin Go
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 22 Pg. 6127-33 (Nov 15 2013) ISSN: 1464-3405 [Electronic] England
PMID24080463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • terameprocol
  • Masoprocol
Topics
  • Antineoplastic Agents (chemistry, pharmacology)
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Masoprocol (analogs & derivatives, chemistry, pharmacology)
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Structure-Activity Relationship
  • Transcriptional Activation (drug effects)

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