New Chemical Matter from Extinct Life and for Extant Life: Paleopharmaceuticals and Bioterrorism Countermeasures

Abstract

Fossils are a promising source of novel drug scaffolds and new drugs, referred to herein as paleopharmaceuticals. Baltic amber, or fossilized resin produced by extinct pines of the family Sciadopityaceae, has been used in traditional medicine to treat a variety of diseases. To explain the medicinal significance of Baltic amber, we report optimized extraction procedures, specifically single rounds of conservative or Soxhlet extraction with dichloromethane. We also present comprehensive surveys of the chemical compositions of Baltic amber and resin from Sciadopitys verticillata, the only extant Sciadopityaceae species. Our analyses using gas chromatography-mass spectrometry showed that Baltic amber and S. verticillata resin are primarily composed of terpenes and terpenoids; however, the identities of these compounds are different because of the chemical transformations that occur during fossilization. The only terpenoid identified in both was verticillol, and this is the first known report of verticillol as a constituent of Baltic amber. Finally, we present in vitro antibacterial activity data for abietane-type diterpenoids like those identified in Baltic amber. These compounds possess significant antibacterial activity against antibiotic-resistant Gram-positive bacterial strains; therefore, abietane-type diterpenoids are a promising drug scaffold for new paleopharmaceuticals.Bacillus anthracis, the causative agent of anthrax, has been identified by the Centers for Disease Control and Prevention as a bioterrorism weapon with significant potential to be a severe threat to public health and safety. Current treatments approved by the Food and Drug Administration for anthrax infections do not target the cause of the lethality and a promising target for the discovery and development of effective anthrax therapeutics: the anthrax toxin lethal factor. While progress has been made toward their development, there are no LF inhibitors currently approved to treat anthrax infections. Recently, we performed an experimental high-throughput screen and identified two compounds with significant LF inhibitory activity. We report the design, synthesis, and evaluation of novel small-molecule LF inhibitors based on these two compounds, increasing their solubility for structural biology studies while maintaining their predicted binding affinities and experimental biological activities.