Synthesis and biological evaluation of geldanamycin analogs against human cancer cells.

Purpose: To find novel potential and less toxic benquinone anamycin heat shock protein 90 (Hsp90) inhibitors as anticancer agents, a limited series of 17-substituted or 17,19-disubstituted 17-demethoxygeldanamycin analogs were synthesized and tested for anti-proliferation activity against human cancer cells. Liver toxicity was also tested in vivo.

Methods: Five 17-alkylamino-17-demethoxygeldanamycins and two 17-alkylamino-19-methylthio-17-demethoxygeldanamycins were synthesized from geldanamycin (GA) and 19-methylthiogeldanamycin (19-S(methyl)-GA), respectively.

[Synthetic biology toward microbial secondary metabolites and pharmaceuticals].

Microbial secondary metabolites are one of the major sources of anti-bacterial, anti-fungal, antitumor, anti-virus and immunosuppressive agents for clinical use. Present challenges in microbial pharmaceutical development are the discovery of novel secondary metabolites with significant biological activities, improving the fermentation titers of industrial microbial strains, and production of natural product drugs by re-establishing their biosynthetic pathways in suitable microbial hosts. Synthetic biology, which is developed from systematic biology and metabolic engineering, provides a significant driving force for microbial pharmaceutical development.

Novel 4,5-dihydro-thiazinogeldanamycin in a gdmP mutant strain of Streptomyces hygroscopicus 17997.

Novel geldanamycin derivative, 4,5-dihydro-thiazinogeldanamycin (3), was characterized from the gdmP mutant in Streptomyces hygroscopicus 17997, besides expected 4,5-dihydro-geldanamycin (2). The presence of this compound would suggest an unknown post-PKS modification in geldanamycin biosynthesis. Compound 3 exhibited moderate anti-HSV-1-virus activity and higher water solubility than geldanamycin (1).

[Deletion of spiramycin 3-O-acyltransferase gene from Streptomyces spiramyceticus F21 resulting in the production of spiramycin I as major component].

Spiramycin (SP) belongs to the 16-member macrolide antibiotics. It contains three components,namely SP I, SP II and SP III, which differ structurally in the acylation moieties on the C3 of the lactone. The SP I component contains a hydroxyl group at C3.