Synthesis and evaluation of antiproliferative activity of a novel series of hydroxychavicol analogs

Eur J Med Chem. 2014 Mar 21;75:1-10. doi: 10.1016/j.ejmech.2014.01.016. Epub 2014 Jan 21.

Abstract

We have recently demonstrated that hydroxychavicol is a major constituent and the most active biophenolic of Piper betel leaves with significant antiproliferative activity in the micro molar range. Herein we present the design, synthesis and evaluation of fifteen novel hydroxychavicol analogs with varying antiproliferative activities in cancer cell lines from two representative tissue types, namely, the prostate and cervix that show very encouraging results compared to the parent compounds. Our long range goal is to develop a structure-activity guided relationship to gain mechanistic insights into novel molecular targets of this class of bioactive molecules for rational drug development. Cytotoxicity-guided experimentation on these novel analogs yielded the following structural factors as the key activity regulators: 1) unlike the hydroxyl substituent at position-4, the position-3 hydroxyl is vital for enhanced activity 2) acetoxyl groups are dispensable for activity as corroborated earlier by others 3) allylic double bonds at 2'C-3'C serve to positively influence antiproliferative activity 4) long saturated side chains at 1'-position negatively regulate antiproliferative activity and 5) maneuvering position-4 with a benzyl group positively impacted the biological activity profile. Most amphiphilic compounds showed moderate to good therapeutic potential as expected on the basis of medicinal chemistry principles. Intriguingly, the most active compound with ten-fold higher activity than the parent molecule was realized by sheer serendipity to employ a silica gel based rearrangement that was further explored using nuclear magnetic resonance spectroscopy and density functional theory calculations. This is the first report to describe strategies for optimal synthesis of a novel series of 15 analogs based upon hydroxychavicol, a simple phytochemical of immense anticancer potential.

Keywords: Anticancer; Antiproliferative; Density functional theory; Hydroxychavicol analogs; Silica gel rearrangement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • Eugenol / analogs & derivatives*
  • Eugenol / chemical synthesis
  • Eugenol / chemistry
  • Eugenol / pharmacology
  • Humans
  • Neoplasms / drug therapy
  • Silica Gel / chemistry
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • 2-hydroxychavicol
  • Eugenol
  • Silica Gel