Identification and Biological Activity of NFAT-133 Congeners from Streptomyces pactum

The soil bacterium Streptomyces pactum ATCC 27456 produces a number of polyketide natural products. Among them is NFAT-133, an inhibitor of the nuclear factor of activated T cells (NFAT) that suppresses interleukin-2 (IL-2) expression and T cell proliferation. Biosynthetic gene inactivation in the ATCC 27456 strain revealed the ability of this strain to produce other polyketide compounds including analogues of NFAT-133. Consequently, seven new derivatives of NFAT-133, TM-129-TM-135, together with a known compound, panowamycin A, were isolated from the culture broth of S. pactum ATCC 27456 Δ ptmTDQ . Their chemical structures were elucidated on the basis of their HRESIMS, 1D and 2D NMR spectroscopy, and ECD calculation and spectral data. NFAT-133, TM-132, TM-135, and panowamycin A showed no antibacterial activity or cytotoxicity, but weakly reduced the production of LPS-induced nitric oxide in RAW264.7 cells in a dose-dependent manner. A revised chemical structure of panowamycin A and proposed modes of formation of the new NFAT-133 analogues are also presented.