Himalaquinones A–G, Angucyclinone-Derived Metabolites Produced by the Himalayan Isolate Streptomyces sp. PU-MM59

Abstract

Himalaquinones A–G, seven new anthraquinone-derived metabolites, were obtained from the Himalayan-based Streptomyces sp. PU-MM59. The chemical structures of the new compounds were identified based on cumulative analyses of HRESIMS and NMR spectra. Himalaquinones A–F were determined to be unique anthraquinones that contained unusual C-4a 3-methylbut-3-enoic acid aromatic substitutions, while himalaquinone G was identified as a new 5,6-dihydrodiol-bearing angucyclinone. Comparative bioactivity assessment (antimicrobial, cancer cell line cytotoxicity, impact on 4E-BP1 phosphorylation, and effect on axolotl embryo tail regeneration) revealed cytotoxic landomycin and saquayamycin analogues to inhibit 4E-BP1p and inhibit regeneration. In contrast, himalaquinone G, while also cytotoxic and a regeneration inhibitor, did not affect 4E-BP1p status at the doses tested. As such, this work implicates a unique mechanism for himalaquinone G and possibly other 5,6-dihydrodiol-bearing angucyclinones.

Biochemical and Structural Studies of the Carminomycin 4-O-Methyltransferase DnrK

“…21 To extend this prior study, a wide range of substituted benzo-γpyrones including representative flavones, flavonols, flavanones, isoflavones, and related scaffolds (Figure 3) were evaluated. The prior docking study with representative flavones [apigenin (43) and luteolin (44)] predicted a preference of DnrK for C7 and C3′. Consistent with this prediction, representative flavones bearing a single free C7-OH [7hydroxyflavone (45) and 5,4′-dimethoxy-7-hydroxyflavone (46)] led to corresponding monomethylated products (12% and 10%, respectively).…”

“…The axolotl embryo tail regeneration assay was conducted following our previously reported protocols. ,, Briefly, stage 42 embryos were manually hatched, administered benzocaine anesthesia (0.2 g in 10 mL of EtOH/L water), and photographed (Figures D and S17). Embryos were subsequently administered 2 mm tail amputations and then reared (in the absence or presence of test agent) at 18–19 °C in 12-well microtiter plates containing 2.0 mL of artificial pond water (43.25 g NaCl, 0.625 g KCl, 1.25 g MgSO 4 , 2.5 g NaHCO 3 , and 1.25 g CaCl per 50 L charcoal filtered municipal water).…”

“…Prior studies in the regenerative salamander model (the Mexican axolotl, Ambystoma mexicanum) revealed tail regeneration to require a rapid escalation of ROS which occurs as a rapid response to axolotl tail amputation. 72 While all members of the test set were well-tolerated in a corresponding axolotl embryo tail regeneration assay, 43,73 only 9 inhibited tail regeneration (Figures 5D and S17). This result highlights subtle anthracycline structural modifications to translate to dramatic shifts in regenerative outcomes where the divergence from the 4E-BP 1p/ROS study described above may result, in part, from yet to be determined factors that contribute to differences in uptake and/or in vivo exposure.…”

Characterization of the Biosynthetic Gene Cluster and Shunt Products Yields Insights into the Biosynthesis of Balmoralmycin

“…The presence of the 3-methylbut-2-enoic acid fragment was reinforced by the HMBC cross-peaks (Figure 1B) between H 2 -4 (δ H 3.69 and 3.65) and C-2 (δ C 119.7)/3-Me (δ C 19.0)/C-5 (δ C 137.7), and between H-2 (δ H 6.16) and C-1 (δ C 169.0)/C-3 (δ C 155.2)/3-Me (δ C 19.0). Given that the Z/E (or tran/cis) geometrical isomers generally display different patterns of proton-proton correlations in the NOESY experiment, the clear NOESY correlation between H-2 and H 2 -4 (Figure 1B) supports that the C2-C3 double bond in 6 adopts an E/trans-configuration, which resembles that of angucycline (E/tran)-himalaquinone-E. 43 The NMR data (Tables S1 and S2) suggest that compound 7 (C 36 H 40 O 10 ) is the methyl ester of 6 with an extra methyl group at C-1.…”

“…In contrast to the E/trans-configuration of C2=C3 bond of 6, the C2=C3 bond adopts a Z/cis-configuration in 7, as supported by the γ-gauche effect-induced upfield shift of C-4 (7: δ C 32.4; 6: δ C 40.1) 43 and the NOESY correlation (Figure 1B) between 3-Me (δ H 1.83) and H-2 (δ H 6.04). Compound 8 has a molecular formula of C 25 H 24 O 9 and the NMR data suggest that 8 lacks the ten-carbon 2,4-decadienoic acid moiety seen in 5 and 6.…”