Natural Products Chemistry
If the microbiologists found biological activity in myxobacteria or fungi the chemist initially analyze the extracts by high-performance liquid chromatography (HPLC) combined with diode-array-UV spectrometry (DAD-UV) and high-resolution mass spectrometry (HR-MS) for antibiotics potentially documented in databases (de-replication). If this is not the case, the new biological activity is isolated as pure compound. Samples of the purified antibiotic are then returned to the microbiologists for further characterization and screening for so far unknown effects in different test systems. Concurrently, the chemists elucidate the structures using ultra-violet (UV), infrared- (IR), mass (MS) and nuclear-magnetic-resonance (NMR) spectra.
For example, Elansolid A1 (1) was isolated as the first macrolide from the gliding bacteria Chitinophaga sancti. From spectrometric data the elemental formula C37H48NO6 and the structure 1 were derived. Later a second Elansolid A2 (1*) was isolated and the structure elucidation provided the same chemical structure (Figure 1). Only the detailed interpretation of the NMR data and the calculation of the 3D structures led to the exceptional result, that both (1/1*) exist as conformational isomers (atropisomers), affixed in two differently folded lactone rings (Figures 2 and 3).
HPLC-UV-MS Analyses of especially mildly and under anhydrous conditions prepared extracts revealed the existence of a third isomer C37H48NO6, the Elansolid A3 (2), which easily is transformed to the atropisomers 1 and 1* as well as to further products. Its structure elucidation resulted in an opened lactone ring and a unusual quinone methide structural unit (Figure 1). Quinone methides are chemically very reactive molecules, which easily add water, amines, alcohols etc.. No one would really expect such a molecule as product of a biosynthesis. Actually, exact this was proven by genetic analysis of the biosynthesis steps (in cooperation with the department Microbial Natural Products (MINS)).
Our chemical studies then showed, that these three molecules are able to interconvert mutually under mild conditions. Even the reactive quinone methide A3 (2) could be recovered from the macrolides A1 and A2 (1 and 1*). With their reactivity the existence of artifact Elansolids as addition and rearrangement products could be explained. The similar biological activity of macrolides and quinone methide also made sense finally.
If really useful drugs are needed for further development as pharmaceuticals or plant protection, like the antitumor agents Epothilon and Disorazol, the antibiotic Sorangicin or the antifungal Soraphen they are produced and isolated in gram scale (50-100 g) by fermentation after biological and chemical process optimization. The products are then provided to external cooperation partners for further development, e.g. for chemical improvement of the activity, and for characterization in preclinical or field studies.
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