ABSTRACT
What often distinguishes the leaders in drug discovery and development from the rest is the quality of their compound libraries and the ease of access that they have to the information within those libraries. The screening of natural products can provide greater structural diversity than standard synthetic chemistry and offers significant opportunities for finding novel low molecular weight lead compounds. However, which strategy is the best for natural-product-based drug discovery? Two well established but relatively time consuming approaches are the screening of crude extracts and pre-fractionated extracts. This case study describes a third, pure-compound-screening approach, and discusses its benefits and pitfalls.
ABSTRACT
Geotrichum candidum can produce and excrete compounds that inhibit Listeria monocytogenes. These were purified by ultrafiltration, centrifugal partition chromatography, thin-layer chromatography, gel filtration, and high-pressure liquid chromatography, and analyzed by liquid chromatography-mass spectrometry, infrared spectrometry, nuclear magnetic resonance spectrometry, and optical rotation. Two inhibitors were identified: D-3-phenyllactic acid and D-3-indollactic acid.
Subject(s)
Anti-Infective Agents/isolation & purification , Lactates/isolation & purification , Lactates/pharmacology , Listeria/drug effects , Mitosporic Fungi/metabolism , Anti-Bacterial Agents , Anti-Infective Agents/pharmacologyABSTRACT
Pepticinnamins A, B, C, D, E and F, a family of farnesyl-protein transferase (FPT) inhibitors were isolated from the fermentation broth of Streptomyces sp. OH-4652. These inhibitors were purified from whole broth by extraction with chloroform, followed by silica gel column chromatography, Sephadex LH-20 chromatography and reverse phase HPLC. Among these, pepticinnamin C showed the most potent inhibition (IC50-100 nM).
Subject(s)
Alkyl and Aryl Transferases , Oligopeptides/isolation & purification , Streptomyces/metabolism , Transferases/antagonists & inhibitors , Animals , Bacteria/drug effects , Cell Division/drug effects , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Fermentation , Microbial Sensitivity Tests , Oligopeptides/biosynthesis , Oligopeptides/pharmacology , Streptomyces/classification , Vero CellsABSTRACT
Structure of novel farnesyl transferase inhibitor, pepticinnamin E, is elucidated by NMR study. Pepticinnamin E is composed of five amino acids and o-pentenylcinnamic acid, having a molecular weight of 907. C-terminal glycylserine of the compounds is in the cyclized diketopiperazine form.
