Design and synthesis of pentacyclic triterpene conjugates and their use in medicinal research

Eur J Med Chem. 2019 Nov 15;182:111653. doi: 10.1016/j.ejmech.2019.111653. Epub 2019 Aug 30.

Abstract

Triterpenoids are natural products from plants and many other organisms that have various biological activities, such as antitumor, antiviral, antimicrobial, and protective activities. This review covers the synthesis and biological evaluation of pentacyclic triterpene (PT) conjugates with other molecules that have been found to increase the IC50 or improve the pharmacological profile of the parent PT. Some of these molecules are designed to target specific proteins or cellular organelles, which has resulted in highly selective lead structures for drug development. Other PT conjugates are useful for investigating their mechanism of action. This concept has been very successful: 1) Many compounds, especially mitochondria-targeting PT conjugates, have reached a selective cytotoxicity at low nanomolar concentrations in cancer cells. 2) A number of PT conjugates have had high activity against HIV or the influenza virus. 3) Fluorescent PT conjugates have been able to visualize the PT in living cells, which has allowed quantification of the uptake and distribution of the PT within the cell. 4) Biotinylated PT conjugates have been used to identify target proteins, which may help to show their mechanism of action. 5) A large number of PT conjugates with polyethylene glycol (PEG), polyamines, etc. form nanometer-sized micelles that have a much better pharmacological profile than the PT alone. In summary, the connection of a PT to an appropriate modifying molecule has resulted in extremely useful semisynthetic compounds with a high potential to treat cancer or viral infections or compounds that are useful for the study of the mechanism of action of PTs at the molecular level.

Keywords: Antiviral; Biological activity; Conjugate; Cytotoxicity; Fluorescence; HIV; Leishmania; Mechanism of action; Mitochondria; Synthesis; Target; Theranostics; Triterpenoid.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Biomedical Research
  • Cell Proliferation / drug effects
  • Drug Design*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • Viruses / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • Antiviral Agents
  • Triterpenes