reblastatin and geldanamycin

The nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin's (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution (trans-lactam), and C, crucial at binding to Hsp90 (cis-lactam). The structure of a new-type conformer B allows to better understand the molecular recognition mechanism between the GDM analogs and the target Hsp90. Combined analysis of: anticancer test results (SKBR-3, SKOV-3, PC-3, U-87, A-549) and those performed in normal cells (HDF), K

Topics: Amines; Antineoplastic Agents; Benzoquinones; Cell Proliferation; Cells, Cultured; Density Functional Theory; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lactams, Macrocyclic; Molecular Structure; Structure-Activity Relationship

Streptomyces autolyticus CGMCC 0516 produces the anti-tumor benzoquinone ansamycins geldanamycin, autolytimycin, and reblastatin and the 16-membered macrodiolide elaiophylin. Here, we report the complete genome sequence of S. autolyticus CGMCC 0516, which consists of a 10,029,028bp linear chromosome and seven circular plasmids. Fifty-seven putative biosynthetic gene clusters for secondary metabolites were found. The geldanamycin, autolytimycin, and reblastatin biosynthetic gene clusters were located on the left arm (2.06-2.15Mb) of the chromosome, and the elaiophylin gene cluster was located on the right arm (9.45-9.53Mb). Twenty-one putative gene clusters with high or moderate similarity to important antibiotic biosynthetic gene clusters were found, including the antitumor agents echoside, bafilomycin, hygrocin, and toxoflavin; the antibacterial/antifungal agents nigericin, skyllamycin, kanamycin, naphthomycin, eco-02301, and bottromycin A2; the immunosuppressants meridamycin and brasilicardin A; the anti-inflammatory agent cyclooctatin; and the acute iron poisoning medication desferrioxamine B. The genome sequence reported here will enable us to study the biosynthetic mechanism of these important antibiotics and will facilitate the discovery of novel secondary metabolites with potential applications to human health.

Topics: Benzoquinones; Genome, Bacterial; Lactams, Macrocyclic; Macrolides; Multigene Family; Quinones; Streptomyces

Topics: Bacterial Proteins; Benzoquinones; Hep G2 Cells; Humans; Lactams, Macrocyclic; Mutation; Quinones; Spores, Bacterial; Streptomyces

Hsp90 is an attractive chemotherapeutic target because it is essential to maturation of multiple oncogenes. We describe the conformational significance of EH21A1-A4, phenolic derivatives of geldanamycin isolated from Streptomyces sp. Their native free structures are similar to the active form of geldanamycin bound to Hsp90 protein. Their conformational character is a probable reason for their high-affinity binding. Lack of toxic benzoquinone in EH21A1-A4 also adds to their potential as lead compounds for anti-tumor drugs.

Topics: Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Models, Molecular; Molecular Structure; Streptomyces

We describe the isolation and characterisation of novel non-benzoquinone ansamycin metabolites related to geldanamycin from a culture of Streptomyces sp. S6699. The compounds possess potent inhibitory activity in a cell-based assay measuring inhibition of oncostatin M signalling in a reporter cell line utilising a secreted placental alkaline phosphatase (sPAP) readout. In this paper we report the isolation and structure elucidation of the compounds and describe some of their biological properties.

Topics: Alkaline Phosphatase; Anti-Bacterial Agents; Benzoquinones; Cell Line; Cell Survival; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Interleukin-6; Lactams, Macrocyclic; Lung; Oncostatin M; Peptides; Protein Biosynthesis; Proteins; Quinones; Recombinant Proteins; Rifabutin; Signal Transduction; Streptomyces