Design and preliminary structure-activity relationship of redox-silent semisynthetic tocotrienol analogues as inhibitors for breast cancer proliferation and invasion

Bioorg Med Chem. 2010 Jan 15;18(2):755-68. doi: 10.1016/j.bmc.2009.11.054. Epub 2009 Nov 27.

Abstract

Vitamin E (VE) is a generic term that represents a family of compounds composed of various tocopherol and tocotrienol isoforms. Tocotrienols display potent anti-angiogenic and antiproliferative activities. Redox-silent tocotrienol analogues also display potent anticancer activity. The ultimate objective of this study was to develop semisynthetically C-6-modified redox-silent tocotrienol analogues with enhanced antiproliferative and anti-invasive activities as compared to their parent compound. Examples of these are carbamate and ether analogues of alpha-, gamma-, and delta-tocotrienols (1-3). Various aliphatic, olefinic, and aromatic substituents were used. Steric limitation, electrostatic, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) properties were varied at this position and the biological activities of these derivatives were tested. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies were performed using Comparative Molecular Field (CoMFA) and Comparative Molecular Similarity Indices Analyses (CoMSIA) to better understand the structural basis for biological activity and guide the future design of more potent VE analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / pathology*
  • Cell Proliferation / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neoplasm Invasiveness
  • Oxidation-Reduction
  • Quantitative Structure-Activity Relationship
  • Stereoisomerism
  • Tocotrienols / chemical synthesis*
  • Tocotrienols / chemistry
  • Tocotrienols / pharmacology*

Substances

  • Antineoplastic Agents
  • Tocotrienols