Advances of the novel immunosuppressant brasilicardin A / 生物工程学报

Brasilicardin A (BraA) is a natural diterpene glycoside isolated from the pathogenic actinomycete Nocardia brasiliensis IFM 0406 with highly potent immunosuppressive activity (IC50=0.057 μg/mL). BraA potently inhibits the uptake of amino acids that are substrates for amino acid transport system L of T cells, which is different from the existing clinical immunosuppressants. BraA is more potent in a mouse mixed lymphocyte reaction and less toxic against various human cell lines compared with the known clinical immunosuppressants, such as cyclosporin A, ascomycin and tacrolimus. Therefore, BraA attracted more attention as a new promising immunosuppressant. However, the development of this promising immunosuppressant as drug for medical use is so far hindered because BraA has the unusual and synthetically challenging skeleton and shows the low-yield production in the natural pathogenic producer. This review introduces the molecular structure of BraA, its activity, mechanism of action, chemical synthesis of BraA analogs, heterologous expression of gene cluster, and an application of combining microbial and chemical synthesis for production of BraA, with the aim to facilitate the efficient production of BraA and its analogs.

Cangumycins A-F, six new angucyclinone analogues with immunosuppressive activity from Streptomyces / 中国天然药物

Cangumycins A-F (1-6), six new angucyclinone analogues, together with two known ones (7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Among them, cangumycins E (5) and F (6) share a C-ring cleaved backbone, and cangumycins B (2) and E (5) exhibit potent immunosuppressive activity (IC 8.1 and 2.7 μmol·L, respectively) against human T cell proliferation at a non-cytotoxic concentration.

Differential Effects of Tautomycetin and Its Derivatives on Protein Phosphatase Inhibition, Immunosuppressive Function and Antitumor Activity

In the present work, we studied the structure-activity relationship (SAR) of tautomycetin (TMC) and its derivatives. Further, we demonstrated the correlation between the immunosuppressive fuction, anticancer activity and protein phosphatase type 1 (PP1) inhibition of TMC and its derivatives. We have prepared some TMC derivatives via combinatorial biosynthesis, isolation from fermentation broth or chemical degradation of TMC. We found that the immunosuppressive activity was correlated with anticancer activity for TMC and its analog compounds, indicating that TMC may home at the same targets for its immunosuppressive and anticancer activities. Interestingly, TMC-F1, TMC-D1 and TMC-D2 all retained significant, albeit reduced PP1 inhibitory activity compared to TMC. However, only TMC-D2 showed immunosuppressive and anticancer activities in studies carried out in cell lines. Moreover, TMC-Chain did not show any significant inhibitory activity towards PP1 but showed strong growth inhibitory effect. This observation implicates that the maleic anhydride moiety of TMC is critical for its phosphatase inhibitory activity whereas the C1-C18 moiety of TMC is essential for the inhibition of tumor cell proliferation. Furthermore, we measured in vivo phosphatase activities of PP1 in MCF-7 cell extracts treated with TMC and its related compounds, and the results indicate that the cytotoxicity of TMC doesn't correlate with its in vivo PP1 inhibition activity. Taken together, our study suggests that the immunosuppressive and anticancer activities of TMC are not due to the inhibition of PP1. Our results provide a novel insight for the elucidation of the underlying molecular mechanisms of TMC's important biological functions.

Diterpenoids possessed immunosuppressive activity from Tripterygium hypoglaucum / 中草药

Objective To study the diterpenoids possessed immunosuppressive activity from Tripterygium hypoglaucum. Methods The chemical constituents were isolated from the CHCl3 extracts of T. hypoglaucum by repeated column chromatography, including silica gel, Sephadex LH-20, and preparative HPLC. Their structures were elucidated on the basis of spectroscopic studies. The immunosuppressive activity of these compounds was tested using the lymphocyte transformation test. Results Compounds Ⅰ-Ⅵ were identified as triptobenzene H (Ⅰ), triptoquinone A (Ⅱ), triptoquinone B (Ⅲ), triptoquinone H (Ⅳ), triptonediol (Ⅴ), triptonoterpene (Ⅵ). Conclusion Compound Ⅰ-Ⅲ are isolated from this medicinal plant for the first time and all the compounds show the significant immunosuppressive activity.