Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli - Production, isolation, physico-chemical and biological properties

New cytostatic compounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciform is. The compounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active a gainst bacteria and only little against fungi, but showed high cytostatic a ctivity against mammalian cell lines with IC50 values in the picomolar rang e. An incubation with 50 ng/ml tubulysin A led to a complete disappearance of the microtubuli network of the cells within 24 hours. The more active tu bulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showe d more than four spindle poles.