Crystal Structures of Actinomycin D and Actinomycin Z3

Untwinned single crystals of the actinomycins D and Z₃ that diffracted to atomic resolution could be obtained for the first time. Low-temperature data collection and a new ab initio method for solving the structures led to precise crystal structures which showed, for example, that the unit cell of actinomycin D contains three molecules, two of which are present in the form of a hydrogen-bridged dimer related by a pseudo-twofold axis (see picture).     

Three-dimensional structure of the actinomycins.

Many complicated three-dimensional structures can be formulated for the actinomycins, red chromopeptide antibiotics distinguished by pronounced antineoplastic activity, because of their unique constitutional type. Since these structures largely determine the specific activity of the actinomycin molecules in the host cells, knowledge of the structural forms occurring naturally in solution is a decisive prerequisite for detailed insight into the mode of biological action of the actinomycins. Investigations by several methods have shown that, in spite of their deviating primary structures, all important actinomycins assume only one very characteristic, pseudo-C₂-symmetrical, and remarkably stable three-dimensional structural type.     

Anti-MRSA actinomycins D1-D4 from the marine sponge-associated Streptomyces sp. LHW52447

Actinomycins D₁?D₄ (1–4), four new D-type actinomycin analogues, were isolated from the fermentation broth of a strain of marine sponge-associated Streptomyces sp. LHW52447, together with actinomycin D (5). The structures of 1?4 were determined by a combination analysis of HRMS and NMR spectroscopic methods, and their absolute configurations of amino acids were determined by Marfey's analysis. Actinomycins D₁ (1) and D₂ (2) are the first two naturally occurring actinomycins with incorporation an oxazole unit into the central phenoxazinone chromophore. Both 1 and 2 showed more potent antibacterial activities against three strains of pathogenic methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 0.125–0.25?μg/mL than those of 3?5 with MIC values of 0.5–1.0?μg/mL, which suggested that the anti-MRSA activity might be enhanced by the incorporation of an additional oxazole unit. In addition, the cytotoxicity evaluation against WI-38 human diploid lung fibroblasts revealed that the incorporation of oxazole unit could decrease the cytotoxicity of actinomycins on human normal cells.