Benwamycins A–G, Trialkyl-Substituted Benzene Derivatives from a Soil-Derived Streptomyces

Abstract

Seven new trialkyl-substituted benzene derivatives named benwamycins A−G (1−7), together with three known congeners, 8−10, were isolated from culture broth of the soilderived Streptomyces sp. KIB-H1471. Their structures were elucidated by using 1D and 2D NMR analyses in combination with HRESIMS data. The absolute configurations of 1−9 were determined by chemical conversion and comparison of circular dichroism spectra and confirmed for 1 by single-crystal X-ray crystallography. Compounds 6 and 7 have a unique γ-pyrone-like ring on one side chain. Compounds 2 and 6 inhibited human T cell proliferation with IC 50 values of 14.3 and 12.5 μM, respectively, without obvious cytotoxicity for nai ̈ve human T cells. Compounds 3 and 6 could weakly enhance insulin-stimulated glucose uptake.

Antidiabetic profiling of veramycins, polyketides accessible by biosynthesis, chemical synthesis and precursor-directed modification

“…The central Weinreb amide building block 26, resulting from oxazolidinone cleavage of 37, was reacted with freshly prepared 27 pinacol boronate 34 under further improved Suzuki conditions (with 3 mol% of XPhos Pd G4 as catalyst) to give intermediate 38 in 96% yield. Conversion of 38 to the corresponding methyl ketone 39 followed by removal of the TBS group finally furnished NFAT-133 (1) in 9 steps and 25% overall total yield (from commercially available starting materials) with all spectroscopic data 11,12,15,17 and optical rotation ([α] 22 D = +40, c = 0.45, MeOH; lit. 17 Reaction of 43 with either tert-butyl ester 44 or TMSE ester 45 under directed Claisen conditions 28 furnished the cyclization precursors 24 and 46 in 84% and 94% yield, respectively.…”

“…14 Very recently, NFAT-133 and several related small polyketides, the benwamycins, were isolated from another soilderived Streptomyces species. 15 While the preparation of our manuscript about investigations on the isolation, characterization, biosynthesis and total synthesis of NFAT-133 and its congeners, the BGC corresponding to NFAT-133 production in Streptomyces pactum was published along with the disclosure of further congeners (Chart 1). 16 The 2D structure of NFAT-133 was determined in 1995 11 but only in 2016, a first proposal of the absolute configuration of NFAT-133 was published based on data obtained from NOESY experiments, J-based configuration analysis ( JBCA) and advanced Mosher's analysis.…”

Biosynthesis of the Nuclear Factor of Activated T Cells Inhibitor NFAT-133 in Streptomyces pactum

“…Benwamycins A–I ( 4 – 12 ) were isolated from Streptomyces sp. KIB-H1471 . Among them, benwamycins B ( 5 ) and F ( 9 ) exhibited antiproliferation activity on human T-cells without appreciable cytotoxicity against naïve human T cells.…”

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

“…K07-0010, and NFAT-133/conglobatin hybrid compounds, TM-127 and TM-128, from S. pactum ATCC 27456. 14,18,19 Benwamycins B and F showed antiproliferation activity on human T-cells activated with anti-CD3/anti-CD28 antibodies without appreciable cytotoxicity against nai ̈ve human T cells, 18 whereas panowamycins A and B showed moderate antitrypanosomal activity. 14 As part of an effort to mine new natural products from soil bacteria, we investigated minor metabolites produced by a mutant strain of S. pactum 129−TM-135, and the biological activities of some of the new compounds are also presented.…”

“…KIB-H1471, panowamycins from Streptomyces sp. K07-0010, and NFAT-133/conglobatin hybrid compounds, TM-127 and TM-128, from S. pactum ATCC 27456. ,, Benwamycins B and F showed antiproliferation activity on human T-cells activated with anti-CD3/anti-CD28 antibodies without appreciable cytotoxicity against naïve human T cells, whereas panowamycins A and B showed moderate antitrypanosomal activity …”