Hartwig Muller

Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds

The potential of new natural products as an important source for the exploration and development of new drugs and crop protection products is a long way from being exhausted. The statistical analysis of the structures of the natural and synthetically derived compounds has shown conspicuous variations in structural types in the natural products derived from different natural sources, which can be utilized in the search for individual active substances. The occasionally voiced prepossession that natural products have already been sufficiently examined and therefore no more innovations are to be expected can definitely be rejected.

Antifungal actinomycete metabolites discovered in a differential cell-based screening using a recombinant TOPO1 deletion mutant strain

In the course of a natural product screening for inhibitors of fungal topoisomerase 1 (TOPO 1), extracts from the actinomycete strains WS 1410 and BS 1465 exhibited promising activities. Bioguided fractionation of the culture broth by preparative HPLC methods yielded the collismycins A (1) and B (2) as active principles of strain WS 1410. Out of the mycelial extracts of strain BS 1465 the bioactive new natural products, cyclo‐homononactic acid (3) and cyclo‐nonactic acid (5) and the structurally related but inactive homononactic acid (4), were isolated. Both collismycin isomers inhibited the recombinant yeast strains ScAL 141 and ScAL 143 (TOPO 1 deletion mutant) in a non‐specific manner with an MIC in the range of 2 μg/ml. The novel cyclo‐homononactic acid (3) and cyclo‐nonactic acid (5) showed higher selectivity towards the wild type strain (MIC = 2 μg/ml as compared to 10μmg/ml for the deletion mutant). All compounds obviously address a target other than TOPO 1 since they do not exhibit activities in a concurrent TOPO 1 enzyme assay.

Identification of alkaloids and polyketides in an Actinomycete by high-performance liquid chromatography with mass spectrometric and UV–Visible detection

Abstract Analytical HPLC with UV–Vis diode array detection and positive electrospray HPLC–MS were employed to characterise the secondary metabolites of Actinomycetes spec. strain BA 909 in crude mycelial extracts and preparative HPLC fractions. It was shown that the strain produced two families of antibiotics previously reported in the literature, namely the polyketides leptomycin A ( 1 ) and B ( 2 ), kazusamycins A ( 3 ) and B ( 4 ) and the alkaloids nybomycin ( 5 ) and deoxynybomycin ( 6 ), respectively. Compounds 1 – 4 were identified by comparison of their HPLC–UV and HPLC–MS data with authentic materials obtained from the original producer strain, whereas the identity of the nybomycins 5 and 6 was established by comparison of structural data with those of reference compounds. From HPLC–UV–Vis analyses it was established that both groups of metabolites are produced as complex mixtures of congeners. The employment of a single HPLC–UV–Vis method, aided by HPLC–MS of selected fractions, allowed for simultaneous detection of the main metabolites in the crude extracts during fermentation. Known metabolites could be distinguished from tentatively new congeners. For example, the data available from HPLC–UV–Vis and HPLC–MS analyses point towards the presence of an anguinomycin A ( 7 ) isomer, two new isomers of kazusamycins A and B ( 8 and 9 ), and a new nybomycin derivative ( 1 0 ) in addition to the known compounds 1 – 6 . The co-occurrence of both leptomycin and nybomycin type metabolites in the same Actinomycete strain was observed for the first time.