Unexpected stereochemical tolerance for the biological activity of tyroscherin

Bioorg Med Chem. 2011 Mar 1;19(5):1708-13. doi: 10.1016/j.bmc.2011.01.027. Epub 2011 Jan 19.

Abstract

Here we describe the concise syntheses of the 15 diastereomers and key analogs of the natural product tyroscherin. While systematic analysis of the analogs clearly demonstrated that the hydrocarbon tail is important for biological activity, structure-activity relationship studies of the complete tyroscherin diastereoarray revealed a surprisingly expansive stereochemical tolerance for the cytotoxic activity. Our results represent a departure from the tenet that biological activity is constrained to a narrow pharmacophore, and highlight the recently emerging appreciation for stereochemical flexibility in defining the essential structural elements of biologically active small molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epinephrine / analogs & derivatives*
  • Epinephrine / chemical synthesis
  • Epinephrine / chemistry
  • Epinephrine / pharmacology
  • Fatty Alcohols / chemical synthesis*
  • Fatty Alcohols / chemistry
  • Fatty Alcohols / pharmacology*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Fatty Alcohols
  • tyroscherin
  • Epinephrine